Organic Compounds

ABSTRACT

The present invention provides a compound of formula I: 
     
       
         
         
             
             
         
       
     
     Said compound is inhibitor of aldosterone synthase and aromatase, and thus can be employed for the treatment of a disorder or disease mediated by aldosterone synthase or aromatase. Accordingly, the compound of formula I can be used in treatment of hypokalemia, hypertension, congestive heart failure, atrial fibrillation, renal failure, in particular, chronic renal failure, restenosis, atherosclerosis, syndrome X, obesity, nephropathy, post-myocardial infarction, coronary heart diseases, inflammation, increased formation of collagen, fibrosis such as cardiac or myocardiac fibrosis and remodeling following hypertension and endothelial dysfunction, gynecomastia, osteoporosis, prostate cancer, endometriosis, uterine fibroids, dysfunctional uterine bleeding, endometrial hyperplasia, polycystic ovarian disease, infertility, fibrocystic breast disease, breast cancer and fibrocystic mastopathy. Finally, the present invention also provides a pharmaceutical composition.

The present invention relates to novel imidazole derivatives that areused as aldosterone synthase and aromatase inhibitors, as well as fortreatment of a disorder or disease mediated by aldosterone synthase oraromatase.

The present invention provides a compound of formula (I)

wherein

-   -   n is 1, or 2, or 3;    -   R is hydrogen, (C₁-C₇) alkyl, or (C₁-C₇) alkenyl, said (C₁-C₇)        alkyl and (C₁-C₇) alkenyl being optionally substituted by one to        five substituents independently selected from the group        consisting of —O—R₈ and —N(R₈)(R₉), wherein R₈ and R₉ are        independently selected from the group consisting of hydrogen,        (C₁-C₇) alkyl, acyl, aryl and heteroaryl, each of which is        further optionally substituted by one to four substituents        independently selected from the group consisting of halo,        (C₁-C₇) alkoxy and (C₁-C₇) alkyl; or    -   R is —C(O)O—R₁₀, or —C(O)N(R₁₁)(R₁₂), wherein R₁₀, R₁₁ and R₁₂        are selected independently from the group consisting of        hydrogen, (C₁-C₇) alkyl, (C₃-C₈) cycloalkyl, aryl, aryl-(C₁-C₇)        alkyl, (C₁-C₇) haloalkyl and heteroaryl, each of which is        further optionally substituted by one to four substituents        independently selected from the group consisting of halo,        hydroxyl, (C₁-C₇) alkoxy, (C₁-C₇) alkyl, and aryl, wherein R₁₁        and R₁₂ taken together with the nitrogen atom to which they are        attached optionally form a 3-8-membered ring;    -   R₁, R₂, R₃, R₄, and R₅ are selected independently from the group        consisting of hydrogen, (C₁-C₇) alkenyl, (C₁-C₇) alkyl, (C₃-C₈)        cycloalkyl, halo, cyano, nitro, H₂N—, (C₁-C₇) haloalkyl, (C₁-C₇)        alkoxy, (C₃-C₈) cycloalkoxy, aryloxy, aryl, heretoaryl,        —C(O)OR₁₀, and —N(R₁₃)(R₁₄), said (C₁-C₇) alkyl, (C₁-C₇)        alkenyl, (C₁-C₇) alkoxy, aryl and heteroaryl being further        optionally substituted by one to three substituents selected        from (C₁-C₇) alkyl, hydroxyl, halo, (C₁-C₇) alkoxy, nitro,        cyano, (C₁-C₇) dialkylamino, (C₁-C₇) alkoxy-(C₁-C₇) alky-, and        (C₁-C₇) haloalkyl, said R₁₀ having the same meanings as defined        above, said R₁₃ and R₁₄ are independently selected from the        group consisting of hydrogen, (C₁-C₇) alkyl, (C₃-C₈) cycloalkyl,        (C₁-C₇) haloalkyl, (C₁-C₇) haloalkoxy, aryl and cyano, with the        proviso that no more than three of R₁, R₂, R₃, R₄, and R₅ are        simultaneously hydrogen;    -   R₁₃ and R₁₄ taken together with the nitrogen atom to which they        are attached optionally form a 3-8-membered ring;    -   R and R₁ taken together optionally form a 5-6-membered ring        containing 0 or 1 heteroatom selected from O, N, or S;    -   R₆ and R₇ are independently hydrogen, hydroxyl, (C₁-C₇) alkyl,        (C₁-C₇) alkoxy, phenyl, or benzyl, wherein phenyl and benzyl are        optionally substituted by one to four substituents independently        selected from the group consisting of halo, (C₁-C₇) alkoxy and        (C₁-C₇) alkyl;    -   when R₆ and R₇ are attached to the same carbon atom, they        optionally form a moiety (A) represented by the following        structure:

-   -   wherein R_(a) and R_(b) are independently hydrogen, (C₁-C₇)        alkyl, (C₁-C₇) alkoxy, acyl, —COOR₁₆ or —COR₁₅, said R₁₅ being        hydrogen, (C₁-C₇) alkyl, (C₁-C₇) haloalkyl, aryl, or —NH₂; or    -   when R₆ and R₇ are attached to the same carbon atom, they taken        together with said carbon atom optionally form a 3-8-membered        ring; or    -   a pharmaceutically acceptable salt thereof; or an optical isomer        thereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula (I),wherein R is hydrogen, (C₁-C₄) alkyl, (C₁-C₄) alkenyl, —C(O)O—R₁₀, or—C(O)N(R₁₁)(R₁₂), said (C₁-C₄) alkyl and (C₁-C₄) alkenyl are optionallysubstituted by one to three substituents independently selected fromhydroxyl, (C₁-C₄) alkoxy, halo, —NH₂, or (C₁-C₄) dialkylamino;

wherein R₁₀, R₁₁ and R₁₂ are independently hydrogen, (C₁-C₄) alkyl,(C₆-C₁₀) aryl-(C₁-C₄) alkyl-, (C₃-C₈) cycloalkyl, or (C₁-C₄) alkenyl,each of which is optionally substituted by one to three substituentsindependently selected from halo, hydroxyl, or (C₁-C₄) alkoxy; whereinR₁₁ and R₁₂ taken together with the nitrogen atom to which they areattached optionally form a 3-8-membered ring;

R₁, R₂, R₃, R₄, and R₅ are independently selected from hydrogen, halo,cyano, —NH₂, (C₁-C₄) dialkylamino, (C₁-C₄) alkoxy, (C₁-C₄) alkenyl,(C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₆-C₁₀) aryl, or (5-9)-memberedheteroaryl, said (C₁-C₄) alkoxy, (C₁-C₄) alkenyl, (C₁-C₄) alkyl and(C₆-C₁₀) aryl being optionally substituted by one to three substituentsindependently selected from halo, (C₁-C₄) alkoxy, (C₁-C₄) alkyl, —NH₂,cyano, nitro, (C₁-C₄) alkoxy-(C₁-C₄) alkyl-, or (C₁-C₄) haloalkyl, withthe proviso that no more than three of R₁, R₂, R₃, R₄, and R₅ aresimultaneously hydrogen; R and R₁ taken together optionally form a5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S;

R₆ and R₇ are independently hydrogen, (C₁-C₄) alkyl, (C₃-C₈) cycloalkyl,(C₁-C₄) alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionallysubstituted by one to three substituents independently selected fromhalo, (C₁-C₄) alkyl, or (C₁-C₄) alkoxy;

when R₆ and R₇ are attached to the same carbon atom, they optionallyform a moiety (A) described above, wherein R_(a) and R_(b) areindependently hydrogen, or (C₁-C₄) alkyl, or R_(a) and R_(b) takentogether with said carbon atom optionally form a 3-8-membered ring; or apharmaceutically acceptable salt thereof; or an optical isomer thereof;or a mixture of optical isomers.

In one embodiment, the present invention provides a compound of formula(II)

wherein

-   -   R, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ have the same meanings as those        defined for formula (I) above, or    -   a pharmaceutically acceptable salt thereof; or an optical isomer        thereof; or a mixture of optical isomers thereof; or a mixture,        of optical isomers thereof.

Preferably, the present invention provides the compound of formula (II),wherein R is hydrogen, (C₁-C₄) alkyl, (C₁-C₄) alkenyl, —C(O)O—R₁₀, or—C(O)N(R₁₁)(R₁₂), said (C₁-C₄) alkyl and (C₁-C₄) alkenyl are optionallysubstituted by one to three substituents independently selected fromhydroxyl, (C₁-C₄) alkoxy, halo, —NH₂, or, (C₁-C₄) dialkylamino;

wherein R₁₀, R₁₁ and R₁₂ are independently hydrogen, (C₁-C₄) alkyl,(C₆-C₁₀) aryl-(C₁-C₄) alkyl-, (C₃-C₈) cycloalkyl, or (C₁-C₄) alkenyl,each of which is optionally substituted by one to three substituentsindependently selected from halo, hydroxyl, or (C₁-C₄) alkoxy; whereinR₁₁ and R₁₂ taken together with the nitrogen atom to which they areattached optionally form a 3-8-membered ring;

R₁, R₂, R₃, R₄, and R₅ are independently selected from hydrogen, halo,cyano, —NH₂, (C₁-C₄) dialkylamino, (C₁-C₄) alkoxy, (C₁-C₄) alkenyl,(C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₆-C₁₀) aryl, or (5-9)-memberedheteroaryl, said (C₁-C₄) alkoxy, (C₁-C₄) alkenyl, (C₁-C₄) alkyl and(C₆-C₁₀) aryl being optionally substituted by one to three substituentsindependently selected from halo, (C₁-C₄) alkoxy, (C₁-C₄) alkyl, —NH₂,cyano, nitro, (C₁-C₄) alkoxy-(C₁-C₄) alkyl-, or (C₁-C₄) haloalkyl, withthe proviso that no more than three of R₁, R₂, R₃, R₄, and R₅ aresimultaneously hydrogen; R and R₁ taken together optionally form a5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S;

R₆ and R₇ are independently hydrogen, (C₁-C₄) alkyl, (C₃-C₈) cycloalkyl,(C₁-C₄) alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionallysubstituted by one to three substituents independently selected fromhalo, (C₁-C₄) alkyl, or (C₁-C₄) alkoxy;

when R₆ and R₇ are attached to the same carbon atom, they optionallyform a moiety (A) described above, wherein R_(a) and R_(b) areindependently hydrogen, or (C₁-C₄) alkyl, or R_(a) and R_(b) takentogether with said carbon atom optionally form a 3-8-membered ring; or apharmaceutically acceptable salt thereof; or an optical isomer thereof;or a mixture of optical isomers.

In another embodiment, the present invention provides a compound offormula (III)

wherein

-   -   R, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ have the same meanings as those        defined for formula (I) above, or    -   a pharmaceutically acceptable salt thereof; or an optical isomer        thereof; or a mixture of optical isomers thereof; or a mixture        of optical isomers thereof.

Preferably, the present invention provides the compound of formula(III), wherein R is hydrogen, (C₁-C₄) alkyl, (C₁-C₄) alkenyl,—C(O)O—R₁₀, or —C(O)N(R₁₁)(R₁₂), said (C₁-C₄) alkyl and (C₁-C₄) alkenylare optionally substituted by one to three substituents independentlyselected from hydroxyl, (C₁-C₄) alkoxy, halo, —NH₂, or (C₁-C₄)dialkylamino;

wherein R₁₀, R₁₁ and R₁₂ are independently hydrogen, (C₁-C₄) alkyl,(C₆-C₁₀) aryl-(C₁-C₄) alkyl-, (C₃-C₈) cycloalkyl, or (C₁-C₄) alkenyl,each of which is optionally substituted by one to three substituentsindependently selected from halo, hydroxyl, or (C₁-C₄) alkoxy; whereinR₁₁ and R₁₂ taken together with the nitrogen atom to which they areattached optionally form a 3-8-membered ring;

R₁, R₂, R₃, R₄, and R₅ are independently selected from hydrogen, halo,cyano, —NH₂, (C₁-C₄) dialkylamino, (C₁-C₄) alkoxy, (C₁-C₄) alkenyl,(C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₆-C₁₀) aryl, or (5-9)-memberedheteroaryl, said (C₁-C₄) alkoxy, (C₁-C₄) alkenyl, (C₁-C₄) alkyl and(C₆-C₁₀) aryl being optionally substituted by one to three substituentsindependently selected from halo, (C₁-C₄) alkoxy, (C₁-C₄) alkyl, —NH₂,cyano, nitro, (C₁-C₄) alkoxy-(C₁-C₄) alkyl-, or (C₁-C₄) haloalkyl, withthe proviso that no more than three of R₁, R₂, R₃, R₄, and R₅ aresimultaneously hydrogen; R and R₁ taken together optionally form a5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S;

R₆ and R₇ are independently hydrogen, (C₁-C₄) alkyl, (C₃-C₈) cycloalkyl,(C₁-C₄) alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionallysubstituted by one to three substituents independently selected fromhalo, (C₁-C₄) alkyl, or (C₁-C₄) alkoxy;

when R₆ and R₇ are attached to the same carbon atom, they optionallyform a moiety (A) described above, wherein R_(a) and R_(b) areindependently hydrogen, or (C₁-C₄) alkyl, or R_(a) and R_(b) takentogether with said carbon atom optionally form a 3-8-membered ring; or apharmaceutically acceptable salt thereof; or an optical isomer thereof;or a mixture of optical isomers.

In another embodiment, the present invention provides a compound offormula (IV)

wherein

-   -   R, R₁, R₂, R₃, R₄, R₅, R₆ and R₇ have the same meanings as those        defined for formula (I) above, or    -   pharmaceutically acceptable salts thereof; or an optical isomer        thereof; or a mixture of optical isomers thereof; or a mixture        of optical isomers thereof.

Preferably, the present invention provides the compound of formula (IV),wherein R is hydrogen, (C₁-C₄) alkyl, (C₁-C₄) alkenyl, —C(O)O—R₁₀, or—C(O)N(R₁₁)(R₁₂), said (C₁-C₄) alkyl and (C₁-C₄) alkenyl are optionallysubstituted by one to three substituents independently selected fromhydroxyl, (C₁-C₄) alkoxy, halo, —NH₂, or (C₁-C₄) dialkylamino;

wherein R₁₀, R₁₁ and R₁₂ are independently hydrogen, (C₁-C₄) alkyl,(C₆-C₁₀) aryl-(C₁-C₄) alkyl-, (C₃-C₈) cycloalkyl, or (C₁-C₄) alkenyl,each of which is optionally substituted by one to three substituentsindependently selected from halo, hydroxyl, or (C₁-C₄) alkoxy; whereinR₁₁ and R₁₂ taken together with the nitrogen atom to which they areattached optionally form a 3-8-membered ring;

R₁, R₂, R₃, R₄, and R₅ are independently selected from hydrogen, halo,cyano, —NH₂, (C₁-C₄) dialkylamino, (C₁-C₄) alkoxy, (C₁-C₄) alkenyl,(C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₆-C₁₀) aryl, or (5-9)-memberedheteroaryl, said (C₁-C₄) alkoxy, (C₁-C₄) alkenyl, (C₁-C₄) alkyl and(C₆-C₁₀) aryl being optionally substituted by one to three substituentsindependently selected from halo, (C₁-C₄) alkoxy, (C₁-C₄) alkyl, —NH₂,cyano, nitro, (C₁-C₄) alkoxy-(C₁-C₄) alkyl or (C₁-C₄) haloalkyl, withthe proviso that no more than three of R₁, R₂, R₃, R₄, and R₅ aresimultaneously hydrogen; R and R₁ taken together optionally form a5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S;

R₆ and R₇ are independently hydrogen, (C₁-C₄) alkyl, (C₃-C₈) cycloalkyl,(C₁-C₄) alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionallysubstituted by one to three substituents independently selected fromhalo, (C₁-C₄) alkyl, or (C₁-C₄) alkoxy;

when R₆ and R₇ are attached to the same carbon atom, they optionallyform a moiety (A) described above, wherein R_(a) and R_(b) areindependently hydrogen, or (C₁-C₄) alkyl, or R_(a) and R_(b) takentogether with said carbon atom optionally form a 3-8-membered ring; or apharmaceutically acceptable salt thereof; or an optical isomer thereof;or a mixture of optical isomers.

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 6carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbonatoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representativeexamples of alkyl include, but are not limited to methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,n-decyl and the like.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. As used herein, the term “lower alkoxy” refers to the alkoxygroups having about 1-7 preferably about 1-4 carbons.

As used herein, the term “acyl” refers to a group R—C(O)— of from 1 to10 carbon atoms of a straight, branched, or cyclic configuration or acombination thereof, attached to the parent structure through carbonylfunctionality. Such group may be saturated or unsaturated, and aliphaticor aromatic. Preferably, R in the acyl residue is alkyl, or alkoxy, oraryl, or heteroaryl. Also preferably, one or more carbons in the acylresidue may be replaced by nitrogen, oxygen or sulfur as long as thepoint of attachment to the parent remains at the carbonyl. Examplesinclude but are not limited to, acetyl, benzoyl, propionyl, isobutyryl,t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower acyl refers toacyl containing one to four carbons.

As used herein, the term “cycloalkyl” refers to optionally substitutedsaturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbongroups of 3-12 carbon atoms, each of which may be substituted by one ormore substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl,acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, nitro,cyano, carboxy, alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl,heterocyclyl and the like. Exemplary monocyclic hydrocarbon groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl and cyclohexenyl and the like. Exemplarybicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl,tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like.

As used herein, the term “cycloalkoxy” refers to —O-cycloalkyl groups.

The term “aryl” refers to monocyclic or bicyclic aromatic, hydrocarbongroups having 6-20 carbon atoms in the ring portion. Preferably, thearyl is a (C₆-C₁₀) aryl. Non-limiting examples include phenyl, biphenyl,naphthyl or tetrahydronaphthyl, each of which may optionally besubstituted by 1-4 substituents, such as alkyl, trifluoromethyl,cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)—O—, aryl-O—,heteroaryl-O—, amino, HS—, alkyl-S—, aryl-S—, nitro, cyano, carboxy,alkyl-O—C(O)—, carbamoyl, alkyl-S(O)—, sulfonyl, sulfonamido,heterocyclyl and the like, wherein R is independently hydrogen, alkyl,aryl, heteroaryl, aryl-alkyl-, heteroaryl-alkyl- and the like.

Furthermore, the term “aryl” as used herein, refers to an aromaticsubstituent which can be a single aromatic ring, or multiple aromaticrings that are fused together, linked covalently, or linked to a commongroup such as a methylene or ethylene moiety. The common linking groupalso can be a carbonyl as in benzophenone or oxygen as in diphenyletheror nitrogen as in diphenylamine.

As used herein, the term “carbamoyl” refers to H₂NC(O)—, alkyl-NHC(O)—,(alkyl)₂NC(O)—, aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—,alkyl(heteroaryl)-NC(O)—, aryl-alkyl-NHC(O)—, alkyl(aryl-alkyl)-NC(O)—and the like.

As used herein, the term “sulfonyl” refers to R—SO₂—, wherein R ishydrogen, alkyl, aryl, hereoaryl, aryl-alkyl, heteroaryl-alkyl, aryl-O—,heteroaryl-O—, alkoxy, aryloxy, cycloalkyl, or heterocyclyl.

As used herein, the term “sulfonamido” refers to alkyl-S(O)₂—NH—,aryl-S(O)₂—NH—, aryl-alkyl-S(O)₂—NH—, heteroaryl-S(O)₂—NH—,heteroaryl-alkyl-S(O)₂—NH—, alkyl-S(O)₂—N(alkyl)-, aryl-S(O)₂—N(alkyl)-,aryl-alkyl-S(O)₂—N(alkyl)-, heteroaryl-S(O)₂—N(alkyl)-,heteroaryl-alkyl-S(O)₂—N(alkyl)- and the like.

As used herein, the term “heterocyclyl” or “heterocyclo” refers to anoptionally substituted, fully saturated or unsaturated, aromatic ornonaromatic cyclic group, e.g., which is a 4- to 7-membered monocyclic,7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system,which has at least one heteroatom in at least one carbon atom-containingring. Each ring of the heterocyclic group containing a heteroatom mayhave 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atomsand sulfur atoms, where the nitrogen and sulfur heteroatoms may alsooptionally be oxidized. The heterocyclic group may be attached at aheteroatom or a carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl,1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl and the like.

Exemplary bicyclic heterocyclic groups include indolyl, dihydroidolyl,benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl,benzothlazinyl, quinuclidinyl, quinolinyl, tetrahydroquinolinyl,decahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,decahydroisoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,benzofuryl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, 1,3-dioxo-1,3-dihydroisoindol-2-yl,dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl),phthalazinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl,dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl,acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl,carbolinyl and the like.

The term “heterocyclyl” further refers to heterocyclic groups as definedherein substituted with 1, 2 or 3 substituents selected from the groupsconsisting of the following:

-   -   (a) alkyl;    -   (b) hydroxyl (or protected hydroxy);    -   (c) halo;    -   (d) oxo, i.e., ═O;    -   (e) amino, alkylamino or dialkylamino;    -   (f) alkoxy;    -   (g) cycloalkyl;    -   (h) carboxy;    -   (i) heterocyclooxy, wherein heterocyclooxy denotes a        heterocyclic group bonded through an oxygen bridge;    -   (j) alkyl-O—C(O)—;    -   (k) mercapto;    -   (l) nitro;    -   (m) cyano;    -   (n) sulfamoyl or sulfonamido;    -   (o) aryl;    -   (p) alkyl-C(O)—O—;    -   (q) aryl-C(O)—O—;    -   (r) aryl-S—;    -   (s) aryloxy;    -   (t) alkyl-S—;    -   (u) formyl, i.e., HC(O)—;    -   (v) carbamoyl;    -   (w) aryl-alkyl-; and    -   (x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy,        amino, alkyl-C(O)—NH—, alkylamino, dialkylamino or halogen.

As used herein, the term “sulfamoyl” refers to H₂NS(O)₂—,alkyl-NHS(O)₂—, (alkyl)₂NS(O)₂—, aryl-NHS(O)₂—, alkyl(aryl)-NS(O)₂—,(aryl)₂NS(O)₂—, heteroaryl-NHS(O)₂—, aralkyl-NHS(O)₂—,heteroaralkyl-NHS(O)₂— and the like.

As used herein, the term “aryloxy” refers to both an —O-aryl and an —O—heteroaryl group, wherein aryl and heteroaryl are defined herein.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic- or fused polycyclic-ring system, having 1 to 8heteroatoms selected from N, O or S. Preferably, the heteroaryl is a5-10 or 5-7 membered ring system. Typical heteroaryl groups include 2-or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl,3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-,4-, or 5-pyrimidinyl.

The term “heteroaryl” also refers to a group in which a heteroaromaticring is fused to one or more aryl, cycloaliphatic, or heterocyclylrings, where the radical or point of attachment is on the heteroaromaticring. Nonlimiting examples include but are not limited to 1-, 2-, 3-,5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-,3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-,4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-,6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-,3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl,3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-,2-, 3-, 4-, 5-, 6-, 7-, or 8-4-aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-,7-, or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-,2-, 3-, 4-; 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-,6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2-,3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl,2-, 3-, 4-, 5-, 6-, or 3-, 4-, 5-, 6-, 7-, 8-, 9-, or10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-,6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-,or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl,2-, 4-, or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5-, or8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl,1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-,8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-,or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-,4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-,or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroary groupsinclude, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 5-, 6-, or7-benzothiazolyl.

A heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic.

As used herein, the term “halogen” or “halo” refers to fluoro, chloro,bromo, and iodo.

As used herein, the term “acylamino” refers to acyl-NH—, wherein “acyl”is defined herein.

As used herein, the term “alkoxycarbonyl” refers to alkoxy-C(O)—,wherein alkoxy is defined herein.

As used herein, the term “alkanoyl” refers to alkyl-C(O)—, wherein alkylis defined herein.

As used herein, the term “alkenyl” refers to a straight or branchedhydrocarbon group having 2 to 20 carbon atoms and that contains at leastone double bonds. The alkenyl groups preferably have about 2 to 8 carbonatoms.

As used herein, the term “haloalkyl” refers to an alkyl as definedherein, that is substituted by one or more halo groups as definedherein. Preferably the haloalkyl can be monohaloalkyl, dihaloalkyl orpolyhaloalkyl including perhaloalkyl. A monohaloalkyl can have one iodo,bromo, chloro or fluoro within the alkyl group. Dihaloalkyl andpolyhaloalkyl groups can have two or more of the same halo atoms or acombination of different halo groups within the alkyl. Preferably, thepolyhaloalkyl contains up to 12, 10, or 8, or 6, or 4, or 3, or 2 halogroups. Non-limiting examples of haloalkyl include fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. A perhaloalkyl refersto an alkyl having all hydrogen atoms replaced with halo atoms.

As used herein, the term “haloalkoxy” refers to haloalkyl-O—, whereinhaloalkyl is defined herein.

As used herein, the term “alkylamino” refers to alkyl-NH—, wherein alkylis defined herein.

As used herein, the term “dialkylamino” refers to (alkyl)(alkyl)N—,wherein alkyl is defined herein.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula. Also as used herein, the term “anoptical isomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Additionally, resolvedcompounds whose absolute configuration is unknown can be designated byhigh pressure liquid chromatography (HPLC) retention time (t_(r)) usinga chiral adsorbent. Certain of the compounds described herein containone or more asymmetric centers and may thus give rise to enantiomers,diastereomers, and other stereoisomeric forms that may be defined, interms of absolute stereochemistry, as (R)- or (S)-. The presentinvention is meant to include all such possible isomers, includingracemic mixtures, optically pure forms and intermediate mixtures.Optically active (R)- and (S)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.If the compound contains a double bond, the substituent may be E or Zconfiguration. If the compound contains a disubstituted cycloalkyl, thecycloalkyl substituent may have a cis- or trans-configuration. Alltautomeric forms are also intended to be included.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the biological effectiveness and properties of thecompounds of this invention and, which are not biologically or otherwiseundesirable. In many cases, the compounds of the present invention arecapable of forming acid and/or base salts by virtue of the presence ofamino and/or carboxyl groups or groups similar thereto. Pharmaceuticallyacceptable acid addition salts can be formed with inorganic acids andorganic acids. Inorganic acids from which salts can be derived include,for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, and the like. Organic acids from which salts canbe derived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable base addition salts can be formed with inorganic and organicbases. Inorganic bases from which salts can be derived include, forexample, sodium, potassium, lithium, ammonium, calcium, magnesium, iron,zinc, copper, manganese, aluminum, and the like; particularly preferredare the ammonium, potassium, sodium, calcium and magnesium salts.Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. The pharmaceutically acceptable salts of the presentinvention can be synthesized from a parent compound, a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting free acid forms of these compounds with astoichiometric amount of the appropriate base (such as Na, Ca, Mg, or Khydroxide, carbonate, bicarbonate, or the like), or by reacting freebase forms of these compounds with a stoichiometric amount of theappropriate acid. Such reactions are typically carried out in water orin an organic solvent, or in a mixture of the two. Generally,non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are preferred, where practicable. Lists of additionalsuitable salts can be found, e.g., in Remington's PharmaceuticalSciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985), whichis herein incorporated by reference.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungal,agents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants; sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289-1329, incorporated herein by reference). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.

The term “therapeutically effective amount” of a compound of the presentinvention refers to an amount of the compound of the present inventionthat will elicit the biological or medical response of a subject, orameliorate symptoms, slow or delay disease progression, or prevent adisease, etc., in a preferred embodiment, the “effective amount” refersto the amount that inhibits or reduces expression of either aldosteronesynthase or aromatase.

As used herein, the term “subject” refers to an animal. Preferably, theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In, a preferred embodiment, the subjectis a human.

As used herein, the term “a disorder” or “a disease” refers to anyderangement or abnormality of function; a morbid physical or mentalstate. See Dorland's Illustrated Medical Dictionary, (W.B. Saunders Co.27th ed. 1988).

As used herein, the term “inhibition” or “inhibiting” refers to thereduction or suppression of a given condition, symptom, or disease, or asignificant decrease in the baseline activity of a biological activityor process. Preferably, the condition is due to the abnormal expressionof aldosterone synthase or aromatase and the biological activity orprocess is associated with the abnormal expression of aldosteronesynthase or aromatase.

As used herein, the term “treating” or “treatment” of any disease ordisorder refers in one embodiment, to ameliorating the disease ordisorder (i.e., arresting or reducing the development of the disease orat least one of the clinical symptoms thereof). In another embodiment“treating” or “treatment” refers to ameliorating at least one Physicalparameter, which may not be discernible by the patient. In yet anotherembodiment, “treating” or “treatment” refers to modulating the diseaseor disorder, either physically, (e.g., Stabilization of a discerniblesymptom), physiologically, (e.g., stabilization of a physicalParameter), or both. In yet another embodiment, “treating” or“treatment” refers to preventing or delaying the onset or development orprogression of the disease or disorder.

As used herein, the term “abnormal” refers to an activity or featurewhich differs from a normal activity or feature.

As used herein, the term “abnormal activity” refers to an activity whichdiffers from the activity of the wild-type or native gene or protein, orwhich differs from the activity of the gene or protein in a healthysubject. The abnormal activity can be stronger or weaker than the normalactivity. In one embodiment, the “abnormal activity” includes theabnormal (either over- or under-) production of mRNA transcribed from agene. In another embodiment, the “abnormal activity” includes theabnormal (either over- or under-) production of polypeptide from a gene.In another embodiment, the abnormal activity refers to a level of a mRNAor polypeptide that is different from a normal level of said mRNA orpolypeptide by about 15%, about 25%, about 35%, about 50%, about 65%,about 85%, about 100% or greater. Preferably, the abnormal level of themRNA or polypeptide can be either higher or lower than the normal levelof said mRNA or polypeptide. Yet in another embodiment, the abnormalactivity refers to functional activity of a protein that is differentfrom a normal activity of the wild-type protein, due to mutations in thecorresponding gene. Preferably, the abnormal activity can be stronger orweaker than the normal activity. The mutations can be in the codingregion of the gene or non-coding regions such as transcriptionalpromoter regions. The mutations can be substitutions, deletions,insertions.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated, herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Any asymmetric carbon atom on the compounds of the present invention canbe present in the (R)-, (S)- or (R,S)-configuration, preferably in the(R)- or (S)-configuration. Substituents atoms with unsaturated bondsmay, if possible, be present in cis- (Z)- or trans (E)-form. Therefore,the compounds of the present invention can be in the form of one of thepossible isomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure geometricor optical isomers, diastereomers, racemates, for example, bychromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, the imidazolyl moiety may thusbe employed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Finally, compounds of the present invention are either obtained in thefree form, as a salt thereof, or as prodrug derivatives thereof.

When a basic group is present in the compounds of the present invention,the compounds can be converted into acid addition salts thereof, inparticular, acid addition salts with the imidazolyl moiety of thestructure, preferably pharmaceutically acceptable salts thereof. Theseare formed, with inorganic acids or organic acids. Suitable inorganicacids include but are not limited to, hydrochloric acid, sulfuric acid,a phosphoric or hydrohalic acid. Suitable organic acids include but arenot limited to, carboxylic acids, such as (C₁-C₄)alkanecarboxylic acidswhich, for example, are unsubstituted or substituted by halogen, e.g.,acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g.,oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylicacids, e.g., glycolic, lactic, malic, tartaric or citric acid, such asamino acids, e.g., aspartic or glutamic acid, organic sulfonic acids;such as (C₁-C₄)alkylsulfonic acids, e.g., methanesulfonic acid; orarylsulfonic acids which are unsubstituted or substituted, e.g., byhalogen. Preferred are salts formed with hydrochloric acid,methanesulfonic acid and maleic acid.

When an acidic group is present in the compounds of the presentinvention, the compounds can be converted into salts withpharmaceutically acceptable bases. Such salts include alkali metalsalts, like sodium, lithium and potassium salts; alkaline earth metalsalts, like calcium and magnesium salts; ammonium salts with organicbases, e.g., trimethylamine salts, diethylamine salts,tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts andN-methyl-D-glucamine salts; salts with amino acids like arginine, lysineand the like. Salts may be formed using conventional methods,advantageously in the presence of an ethereal or alcoholic solvent, suchas a lower alkanol. From the solutions of the latter, the salts may beprecipitated with ethers, e.g., diethyl ether. Resulting salts may beconverted into the free compounds by treatment with acids. These orother salts can also be used for purification of the compounds obtained.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention can also form internalsalts.

The present invention also provides pro-drugs of the compounds of thepresent invention that converts in vivo to the compounds of the presentinvention. A pro-drug is an active or inactive compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject. The suitability andtechniques involved in making and using pro-drugs are well known bythose skilled in the art. Prodrugs can be conceptually divided into twonon-exclusive categories, bioprecursor prodrugs and carrier prodrugs.See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth,Academic Press, San Diego, Calif., 2001). Generally; bioprecursorprodrugs are compounds are inactive or have low activity compared to thecorresponding active drug compound, that contains one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollow types:

1. Oxidative reactions, such as oxidation of alcohol, carbonyl, and acidfunctions, hydroxyation of aliphatic carbons, hydroxyation of alicycliccarbon atoms, oxidation of aromatic carbon atoms, oxidation ofcarbon-carbon double bonds, oxidation of nitrogen-containing functionalgroups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-dealkylation, oxidative O- and S-dealkylation, oxidative deamination,as well as other oxidative reactions.

2. Reductive reactions, such as reduction of carbonyl groups, reductionof alcoholic groups and carbon-carbon double bonds, reduction ofnitrogen-containing functions groups, and other reduction reactions.

3. Reactions without change in the state of oxidation, such ashydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogensingle bonds, hydrolytic cleavage of non-aromatic heterocycles,hydration and dehydration at multiple bonds, new atomic linkagesresulting from dehydration reactions, hydrolytic dehalogenation, removalof hydrogen halide molecule, and other such reactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improve uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, and any releasedtransport moiety is acceptably non-toxic. For prodrugs where thetransport moiety is intended to enhance uptake, typically the release ofthe transport moiety should be rapid. In other cases, it is desirable toutilize a moiety that provides slow release, e.g., certain polymers orother moieties, such as cyclodextrins. See, Cheng et al., US20040077595,application Ser. No. 10/656,838, incorporated herein by reference. Suchcarrier prodrugs are often advantageous for orally administered drugs.Carrier prodrugs can, for example, be used to improve one or more of thefollowing properties: increased lipophilicity, increased duration ofpharmacological effects, increased site-specificity, decreased toxicityand adverse reactions; and/or improvement in drug formulation (e.g.,stability, water solubility, suppression of an undesirable organolepticor physiochemical property). For example, lipophilicity can be increasedby esterification of hydroxy groups with lipophilic carboxylic acids, orof carboxylic acid groups with alcohols, e.g., aliphatic alcohols.Wermuth, The Practice of Medicinal Chemistry, Ch. 31-32, Ed. Werriuth,Academic Press, San Diego, Calif., 2001.

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acyland O-acyl derivatives of thiols, alcohols or phenols, wherein acyl hasa meaning as defined herein. Preferred are pharmaceutically acceptableester derivatives convertible by solvolysis under physiologicalconditions to the parent carboxylic acid, e.g., lower alkyl esters,cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- ordi-substituted lower alkyl esters, such as the ω-(amino, mono- ordi-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters,the α-(lower alkanoyloxy, lower alkoxycarbonyl or di-loweralkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethylester and the like conventionally used in the art. In addition, amineshave been masked as arylcarbonyloxymethyl substituted derivatives whichare cleaved by esterases in vivo releasing the free drug andformaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)). Moreover, drugscontaining an acidic NH group, such as imidazole, imide, indole and thelike, have been masked with N-acyloxymethyl groups (Bundgaard, Design ofProdrugs, Elsevier (1985)). Hydroxy groups have been masked as estersand ethers. EP 039,051 (Sloan and Little) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use.

In view of the close relationship between the compounds, the compoundsin the form of their salts and the pro-drugs, any reference to thecompounds of the present invention is to be understood as referring alsoto the corresponding pro-drugs of the compounds of the presentinvention, as appropriate and expedient.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization.

The compounds of the present invention have valuable pharmacologicalproperties. The compounds of the present invention are useful asaldosterone synthase inhibitors. Aldosterone synthase (CYP11B2) is amitcohcondrial cytochrome P450 enzyme catalyzing the last step ofaldosterone production in the adrenal cortex, i.e., the conversion of11-deoxycorticosterone to aldosterone. Aldosterone synthase has beendemonstrated to be expressed in all cardiovascular tissues such asheart, umbilical cord, mesenteric and pulmonary arteries, aorta,endothelium and vascular cells. Moreover, the expression of aldosteronesynthase is closely correlated with aldosterone production in cells. Ithas been observed that elevations of aldosterone activities oraldosterone levels induce different diseases such as congestive heartfailure, cardiac or myocardial fibrosis, renal failure, hypertension,ventricular arrhythmia and other adverse effects, etc., and that theinhibition of aldosterone or aldosterone synthase would be usefultherapeutic approaches. See e.g., Ulmschenider et al. “Development andevaluation of a pharmacophore model for inhibitors of aldosteronesynthase (CYP11B2),” Bioorganic & Medicinal Chemistry Letters, 16: 25-30(2006); Bureik et al., “Development of test systems for the discovery ofselective human aldosterone synthase (CYP11B2) and 11β-hydroxylase(CYP11B1) inhibitors, discovery of a new lead compound for the therapyof congestive heart failure, myocardial fibrosis and hypertension,”Moleculare and Cellular Endocrinology, 217: 249-254 (2004); Bos et al.,“Inhibition of catechnolamine-induced cardiac fibrosis by an aldosteronantagonist,” J. Cardiovascular Pharmacol, 45(1): 8-13 (2005); Jaber andMadias, “Progression of chronic kidney disease: can it be prevented orarrested?” Am. J. Med. 118(12): 1323-1330 (2005); Khan and Movahed, “Therole of aldosterone and aldosterone-receptor antagonists in heartfailure,” Rev. Cardiovasc Med., 5(2): 71-81 (2004); Struthers,“Aldosterone in heart failure: pathophysiology and treatment,” CyrrHeart Fail., 1(4): 171-175 (2004); Harris and Rangan, “Retardation ofkidney failure—applying principles to practice,” Ann. Acad. Med.Singapore, 34(1): 16-23 (2005); Arima, “Aldosterone and the kidney:rapid regulation of renal microcirculation,” Steroids, onlinepublication November 2005; Brown, “Aldosterone and end-organ damage,”Curr. Opin. Nephrol Hypertens, 14:235-241 (2005); Grandi,“Antihypertensive therapy: role of aldosteron antagonists,” Curr.Pharmaceutical Design, 11: 2235-2242 (2005); Declayre and Swynghedauw,“Molecular mechanisms of myocardial remodeling: the role ofaldosterone,” J. Mol. Cell. Cardiol., 34: 1577-1584 (2002). Accordingly,the compounds of the present invention as aldosterone synthaseinhibitors, are also useful for treatment of a disorder or diseasemediated by aldosterone synthase or responsive to inhibition ofaldosterone synthase. In particular, the compounds of the presentinvention as aldosterone synthase inhibitors are useful for treatment ofa disorder or disease characterized by abnormal aldosterone synthaseactivity. Preferably, the compounds of the present invention are alsouseful for treatment of a disorder or disease selected from hypokalemia,hypertension, congestive heart failure, atrial fibrillation, renalfailure, in particular, chronic renal failure, restenosis,atherosclerosis, syndrome X, obesity, nephropathy, post-myocardialinfarction, coronary heart diseases, inflammation, increased formationof collagen, fibrosis such as cardiac or myocardiac fibrosis andremodeling following hypertension and endothelial dysfunction.

Furthermore, the compounds of the present inventions are useful asaromatase inhibitors. Aromatase is a cytochrome P450 enzyme, it plays acentral role in the extragonadal biosynthesis of estrogens such asestradiol, estrone and estrol, and is widely distributed in muscular andadipose tissue (Longcope C, Pratt J H, Schneider S H, Fineberg S E,1977, J. Clin. Endocrinol. Metab. 45:1134-1145). An increase inaromatase activity has been confirmed to be associated withestrogen-dependent disorders or diseases. Accordingly, the compounds ofthe present invention are also useful for treatment of a disorder ordisease characterized by abnormal expression of aromatase. Preferably,the compounds of the present invention are useful for treatment of anestrogen-dependent disorder or disease. More preferably, the compoundsof the present invention are useful for treatment of anestrogen-dependent disorder or disease selected from gynecomastia,osteoporosis, prostate cancer, endometriosis, uterine fibroids,dysfunctional uterine bleeding, endometrial hyperplasia, polycysticovarian disease; infertility, fibrocystic breast disease, breast cancerand fibrocystic mastopathy.

Additionally, the present invention provides:

-   -   a compound of the present invention for use as a medicament;    -   the use of a compound of the present invention for the        preparation of a pharmaceutical composition for the delay of        progression and/or treatment of a disorder or disease mediated        by aldosterone synthase, or responsive to inhibition of        aldosterone synthase, or characterized by abnormal activity or        expression of aldosterone synthase.    -   the use of a compound of the present invention for the        preparation of a pharmaceutical composition for the delay of        progression and/or treatment of a disorder or disease mediated        by aromatase, or responsive to inhibition of aromatase, or        characterized by abnormal activity or expression of aromatase.    -   the use of a compound of the present invention for the        preparation of a pharmaceutical composition for the delay of        progression and/or treatment of a disorder or disease selected        from hypokalemia, hypertension, congestive heart failure, atrial        fibrillation, renal failure, in particular, chronic renal        failure, restenosis, atherosclerosis, syndrome X, obesity,        nephropathy, post-myocardial infarction, coronary heart        diseases, increased formation of collagen, fibrosis such as        cardiac or myocardiac fibrosis and remodeling following        hypertension and endothelial dysfunction.    -   the use of a compound of the present invention for the        preparation of a pharmaceutical composition for the delay of        progression and/or treatment of a disorder or disease selected        from gynecomastia, osteoporosis, prostate cancer, endometriosis,        uterine fibroids, dysfunctional uterine bleeding, endometrial        hyperplasia, polycystic ovarian disease, infertility,        fibrocystic breast disease, breast cancer and fibrocystic        mastopathy.

The compounds of formula (I)-(IV) can be prepared by the proceduresdescribed in the following sections.

Generally, the compounds of formula (II) can be prepared according toScheme 1, which contains 13 steps.

As to the individual steps in the above scheme, step 1 involves theintroduction of a suitable protecting group on N1 of the imidazole of(V), preferably triphenylmethyl, by reacting (V) with a suitable reagentsuch as triphenylmethyl chloride, in the presence of pyridine. Step 2involves the reduction of the carboxylic acid with a suitable reducingreagent, preferably BH₃.THF complex. Step 3 involves the protection ofthe alcohol resulting from step 2 as a silyl ether, preferably ast-butyldimethylsilyl ether, with a suitable reagent such ast-butyldimethylsilyl chloride in the presence of a suitable base,preferably Et₃N or imidazole, and an aprotic solvent, preferably DMF orCH₂Cl₂ to provide (VI).

Alternatively (VI) can be prepared from (V) by a four step sequence. Instep 1 (V) is converted to the corresponding methyl ester upon reactionwith methanol in the presence of an acid, preferably HCl. Step 2involves the protection of N1 of the imidazole, preferably withtriphenylmethyl, upon reaction with triphenylmethyl chloride in thepresence of a suitable base, preferably Et₃N. Step 3 involves thereduction of the ester formed in step 1 upon reaction with a suitablereducing reagent, preferably LiAlH₄, in an aprotic solvent, preferablyTHF. Step 4 involves the protection of the resulting alcohol moiety as asilyl ether to as described in step 3 of the preceding paragraph toprovide (VI).

Step 4 involves the reaction of a (VI) with the appropriate alkylatingreagent (VII), such as X=Br, in an aprotic solvent, preferably CH₃CN toprovide (VIII). Alkylating agents (VII) or (IX) may be prepared bytreatment of the corresponding toluene or phenyl acetic acid esterderivative with a suitable brominating agent, e.g. NBS, in the presenceof a suitable radical initiator, such as AIBN or benzoyl peroxide.Alternatively, alkylating agents (VII) may be generated by conversion ofa substituted benzyl alcohol to the corresponding halide by treatmentwith, for example, CBr₄ and PPh₃.

Step 6 involves the reaction of (VIII) with a suitable base, preferablyLHMDS, and suitable electrophilic reagent, preferably cyanomethylformateor chloromethylformate. Step 7 involves the removal of thet-butyldimethylsilyl protecting group upon treatment with acid,preferably HCl, to provide ester (X).

Alternatively (X) can be prepared by alkylation of (VI) with anappropriate alkylating reagent (IX), preferably where X=Br, shown instep 5 followed by removal of the silyl protecting group as described instep 7.

Step 8 involves conversion of alcohol (X) to a suitable leaving group,preferably mesylate, by reacting (X) with methanesulfonyl chloride inthe presence of a suitable base, preferably Et₃N; and an aproticsolvent, preferably CH₂Cl₂. Step 9 involves the intramolecularalkylation upon reaction of the mesylate from step 8 with a suitablebase, preferably Et₃N, in a polar aprotic solvent, preferably. DMF orCH₃CN, to provide compounds of formula (I) where R=CO₂alkyl.

Additionally, compounds from step 9 where R=CO₂alkyl, can be treatedwith a suitable metal alkoxide, preferably lithium hydroxide in asolvent, for example H₂O and THF, to provide compounds from step 10where R=CO₂H. Step 11 involves decarboxylation of the compounds, whereR=CO₂H upon heating in a suitable solvent, preferably DMSO, to providecompounds from step 12 where R=H.

Additional compounds of formula (I) may be prepared from conversion ofcarboxylic acid (I), where R=CO₂H, into the corresponding acid chlorideupon treatment with a suitable chlorinating reagent, preferably oxalylchloride, in an aprotic solvent, preferably CH₂Cl₂. The acid chlorideobtained is then reacted with the appropriate nucleophile, preferably analcohol or an amine, in the presence of a suitable base to providecompounds of formula (I) where R=CO₂R₁₀ or CO₂NR₁₁NR₁₂ (step 12).

Alternatively, the compounds of formula (II) can be prepared accordingto Scheme 2, which contains four steps.

As to the individual steps in the Scheme 2 above, step 1 involvesreduction of the known carboxylic ester (XI) to the correspondingaldehyde (XII) upon treatment with a suitable reducing reagent,preferably DIBAL-H, and an aprotic solvent, preferably CH₂Cl₂. Step 2involves the reaction of aldehyde (XII) with an appropriateorganometallic reagent (XIII), preferably where M=Li, MgBr, or MgCl, toprovide alcohol (XIV). The organometallic reagents (XIII) are obtainedfrom commercial sources or generated under standard conditions by theaction of a strong base, e.g. n-BuLi.

Step 3 involves the conversion of the alcohol moiety in (XIV) to aleaving group, preferably mesylate, upon reaction of (XIV) withmethanesulfonyl chloride, and a suitable base, preferably Et₃N, in asolvent, preferably CH₂Cl₂. Step 4 involves the intramolecular N3alkylation of the imidazole upon warming the mesylate prepared in step 3in a polar aprotic solvent, preferably CH₃CN or DMF to provide compoundsof formula (II).

Alternatively, the compounds of formula (II) can be prepared from othercompounds of formula (II), where R₁, R₂, or R₃ represent a halogen orpseudo halogen, e.g., bromide or triflate by palladium or coppercatalyzed coupling of a alkyl, alkenyl, or aryl boronic acid, boronicester, or boroxine; organostannane; organozinc; metal alkoxide; alcohol;amide; or the like to yield the corresponding alkyl, cycloalkyl, aryl,heteroaryl, alkoxy, aryloxy, or acylamino analog. These transformationsinvolve the conversion of compounds of formula (II) where R₁, R₂, and/orR₃ may be equal to a halogen or pseudohalogen, such as Br, to compoundsof formula (II) where R₁, R₂, and/or R₃ may be alkyl or aryl by Suzukicross-coupling with a boronic acid, or the like, in the presence of acatalyst, preferably Pd(PPh₃)₄, a base, preferably potassium hydroxideand sodium carbonate, to provide compounds of formula (II). Additionalcompounds of formula (II) are prepared from existing compounds offormula (II) by independent manipulation of radicals R, R₁, R₂, R₃, R₄,and R₅ by methods known to those skilled in the art, such as, forexample, reduction of a nitro group to an aniline or reduction of anester to an alcohol.

Alternatively, the compounds of formula (II) can be prepared accordingto Scheme 3, which contains three steps.

As to the individual steps in Scheme 3, Step 1 involves alkylation of N3of imidazole (XV) with electrophiles (VII) to provide (XVI). Step 2involves the conversion of the alcohol of (XVI) to a leaving group,preferably chloride, upon reaction with a suitable chlorinating reagent,preferably thionyl chloride. Step 3 involves the intramolecularalkylation upon reaction of the chloride resulting from step 2 with abase, preferably LDA, to provide compounds of the formula (II) whereR=H.

Generally, compounds of formula (III) or (IV) can be prepared accordingto Scheme 4 by analogy to the cyclization described above as step 2 and3 in Scheme 3 for the preparation of (II), e.g. by conversion of analcohol (XVII) to a suitable leaving group, preferably the chloridegenerated by treatment with SOCl₂, followed by deprotonation with strongbase, such as t-BuOK, LDA, or LHMDS, or the like, to effect cyclizationof the resultant anion onto the leaving group.

Alternatively, compounds of formula (III) or (IV) can be preparedaccording to Scheme 5, by conversion of a secondary alcohol (XVIIII) toa suitable leaving group, e.g. chloride or mesylate (step 1), andsubsequent intramolecular cyclization (step 2) by analogy to steps 3 and4 of Scheme 2 above.

Additionally, compounds of formula (III) or (IV) are prepared fromexisting compounds of formula (III) or (IV) by independent manipulationof radicals R, R₁, R₂, R₃, R₄, and R₅ by methods known to those skilledin the art, such as, for example, reduction of a nitro group to ananiline or reduction of an ester to an alcohol. For example, compoundsof formula (III) or (IV) can be prepared from other compounds of formula(III) or (IV), where R₁, R₂, or R₃ represent a halogen or pseudohalogen, e.g., bromide or triflate by palladium or copper catalyzedcoupling of an alkyl, alkenyl, or aryl boronic acid, boronic ester, orboroxine; organostannane; organozinc; metal alkoxide; alcohol; amide; orthe like to yield the corresponding alkyl, cycloalkyl, aryl, heteroaryl,alkoxy, aryloxy, or acylamino analog. These transformations involve theconversion of compounds of formula (III) or (IV) where R₁, R₂, and/or R₃may be equal to a halogen or pseudohalogen, such as Br, to compounds offormula (III) or (IV) where R₁, R_(z), and/or R₃ may be alkyl or aryl bySuzuki cross-coupling with a boronic acid, or the like, in the presenceof a catalyst, preferably Pd(PPh₃)₄, a base, preferably potassiumhydroxide and sodium carbonate, to provide compounds of formula (III) or(IV). Additional compounds of formula (III) or (IV) are generated bytreatment of compounds (III) or (IV) when R=H with a strong base, forexample LHMDS, followed by a suitable elecrophile, for example methyliodide or allyl bromide to give compounds of formula (III) or (IV) whereR is not equal to H.

Additionally, compounds of formula (I) are generated from existingcompounds of formula (I) where R and R₁ are not equal to H and R and R₁may be reacted to form compounds where R and R₁ together comprise aring.

Intermediate alcohols (XVII) are prepared by deprotection of a silylether (XIX), preferably a TBS ether, under, for example, acidicconditions or by reduction of the analogous ester (XX), preferably withNaBH₄, according to Scheme 6.

Ethers (XIX) and esters (XX) are generated by N-alkylation of a suitablyprotected imidazoles (XXI) or (XXII), respectively, utilizing a suitableelectrophile (VII) according to Scheme 7.

The N-protected imidazole intermediates (XXI) and (XXII) are preparedaccording to Scheme 8. Esterification of acid (XXIII) with an alcohol,preferably methanol or ethanol, under acidic conditions followed byprotection of the imidazole nitrogen, preferably as the N-trityl analoggives (XXII), with R₈ and R₇ equal to hydrogen. Reduction of (XXII) tothe alcohol by a suitable reducing agent, preferably NaBH₄, followed byprotection as the TBS ether gives (XXI). Esters (XXII) where R₆ and R₇are not both hydrogen are generated by alkylation of esters (XXII) witha suitable electrophile, e.g. a benzyl bromide, under basic conditions.Conversion of the ester (XXII) to ether (XXI) with R₆ and R₇ not bothhydrogen may be effected by reduction and protection of the resultantalcohol by analogy to above. Substituents R₆ and/or R₇ not equal tohydrogen may be introduced to the carbon adjacent to the imidazole bytreatment of ester (XXV) with a suitable base, e.g. LDA, andelectrophile, such as methyl iodide. Esters (XXII) where R₇ equals H maybe generated by Wittig olefination of ketones (XXIV) by analogy tomethods outlined in Bioorg. Med. Chem. 2004, 12(9), 2273. Subsequentreduction of the olefinic moiety with a suitable reducing agent, such ashydrogen, utilizing a palladium catalyst yields ester (XXII). Esters(XXV) are produced by alkylations of esters (XXV) where R₆ and/or R₇ arehydrogen under basic conditions in the presence of a suitableelectrophile, e.g. methyl iodide. Homologation of ester (XXV) to ether(XXI) can be achieved by reduction with a suitable reagent, such as LAH,followed by oxidation to the aldehyde, treatment of the aldehyde withthe ylide generated from methoxymethyl triphenylphosphonium chloride toproduce the homolog aldehyde. Reduction of the aldehyde and subsequentprotection of the alcohol yields ethers (XXI).

Compounds of formula (IV) where R₇ is defined above, are prepared fromaldehyde or ketone (XXIV), by Wittig olefination utilizing a suitablysubstituted phosphonium salt, for example3-(tert-butyldimethylsilyloxy)propyl triphenylphoshonium bromide in thepresence of a base, preferably n-BuLi according to Scheme 9. Reductionof the resultant olefins yields the saturated ether (XXI) with R₆ equalto hydrogen, which may be N-alkylated with a bromide (VII) by analogy tostep 4 outlined in Scheme 1 for the conversion of (VI) to (VIII).

Additionally, substituent R₆ not equal to hydrogen may be introduced tocompounds of formula (IV) according to Scheme 10 by conversion of ester(XXII) to olefin (XXVI) by a three step process: 1) reduction to theprimary alcohol, Swern oxidation to the aldehyde and 3) conversion tothe olefin (XXVI) by Wittig olefination. Cross metathesis of olefin(XXVI) with enone (XXVII) utilizing Grubbs' second generation catalystprovides enone (XXVIII), which undergoes copper-mediated conjugateaddition with a suitable nucleophile, such as an alkylzinc reagent togive saturated ketone (XXIX). Reduction of (XXIX) with a suitablereagent, such as NaBH₄, provides secondary alcohol (XVIII).

Generally, enantiomers of the compounds of the present invention can beprepared by methods known to those skilled in the art to resolve racemicmixtures, such as by formation and recrystallization of diastereomericsalts or by chiral chromatography or HPLC separation utilizing chiralstationery phases.

In starting compounds and intermediates which are converted to thecompounds of the invention in a manner described herein, functionalgroups present, such as amino, thiol, carboxyl and hydroxy groups, areoptionally protected by conventional protecting groups that are commonin preparative organic chemistry. Protected amino, thiol, carboxyl andhydroxyl groups are those that can be converted under mild conditionsinto free amino thiol, carboxyl and hydroxyl groups without themolecular framework being destroyed or other undesired side reactionstaking place.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and, choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxyl group,amino group, etc.), the structure and stability of the molecule of whichthe substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, e.g., in McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London, N.Y. (1973); andGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wileyand Sons, Inc., NY (1999).

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluent, preferably, such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents, respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures, preferably ator near the boiling point of the solvents used, and at atmospheric orsuper-atmospheric pressure. The preferred solvents, catalysts andreaction conditions are set forth in the appended illustrative Examples.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known per se.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention and apharmaceutically acceptable carrier. The pharmaceutical composition canbe formulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,etc. In addition, the pharmaceutical compositions of the presentinvention can be made up in a solid form including capsules, tablets,pills, granules, powders or suppositories, or in a liquid form includingsolutions, suspensions or emulsions. The pharmaceutical compositions canbe subjected to conventional pharmaceutical operations such assterilization and/or can contain conventional inert diluents,lubricating agents, or buffering agents, as well as adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers and buffers etc.

Preferably, the pharmaceutical compositions are tablets and gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, silica, talcum, stearic acid, its magnesium or        calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withnontoxic pharmaceutically acceptable excipients which are suitable forthe manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Injectable compositions are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also, contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, preferably about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with carrier. Advantageouscarriers include absorbable pharmacologically acceptable solvents toassist passage through the skin of the host. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound of the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations; e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The pharmaceutical compositions contain a therapeutically effectiveamount of a compound of the invention as defined above, either alone orin a combination with one or more therapeutic agents, e.g., each at aneffective therapeutic dose as reported in the art. Such therapeuticagents include at least one or two or more selected from the followinggroups:

(i) angiotensin II receptor antagonist or a pharmaceutically acceptablesalt thereof,

(ii) HMG-Co-A reductase inhibitor or a pharmaceutically acceptable saltthereof,

(iii) angiotensin converting enzyme (ACE) Inhibitor or apharmaceutically acceptable salt thereof,

(iv) calcium channel blocker (CCB) or a pharmaceutically acceptable saltthereof,

(v) dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP)inhibitor or a pharmaceutically acceptable salt thereof,

(vi) endothelin antagonist or a pharmaceutically acceptable saltthereof,

(vii) renin inhibitor or a pharmaceutically acceptable salt thereof,

(viii) diuretic or a pharmaceutically acceptable salt thereof,

(ix) an ApoA-I mimic;

(x) an anti-diabetic agent;

(xi) an obesity-reducing agent;

(xii) an aldosterone receptor blocker;

(xiii) an endothelin receptor blocker;

(xiv) a CETP inhibitor;

(xv) an inhibitor of Na-K-ATPase membrane pump;

(xvi) a beta-adrenergic receptor blocker or an alpha-adrenergic receptorblocker;

(xvii) a neutral endopeptidase (NEP) inhibitor; and

(xviii) an inotropic agent.

An angiotensin II receptor antagonist or a pharmaceutically acceptablesalt thereof is understood to be an active ingredients which bind to theAT₁-receptor subtype of angiotensin II receptor but do not result inactivation of the receptor. As a consequence of the inhibition of theAT₁ receptor, these antagonists can, for example, be employed asantihypertensives or for treating congestive heart failure.

The class of AT₁ receptor antagonists comprises compounds havingdiffering structural features, essentially preferred are thenon-peptidic ones. For example, mention may be made of the compoundswhich are selected from the group consisting of valsartan, losartan,candesartan, eprosartan, irbesartan, saprisartan, tasosartan,telmisartan, the compound with the designation E-1477 of the followingformula

the compound with the designation SC-52458 of the following formula

and the compound with the designation ZD-8731 of the following formula

or, in each case, a pharmaceutically acceptable salt thereof.

Preferred AT₁-receptor antagonist are those agents which have beenmarketed, most preferred is valsartan or a pharmaceutically acceptablesalt thereof.

HMG-Co-A reductase inhibitors (also calledbeta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitors) areunderstood to be those active agents that may be used to lower the lipidlevels including cholesterol in blood.

The class of HMG-Co-A reductase inhibitors comprises compounds havingdiffering structural features. For example, mention may be made of thecompounds that are selected from the group consisting of atorvastatin,cerivastatin, compactin, dalvastatin, dihydrocompactin, fluindostatin,fluvastatin, lovastatin, pitavastatin, mevastatin, pravastatin,rivastatin, simvastatin, and velostatin, or, in each case, apharmaceutically acceptable salt thereof.

Preferred HMG-Co-A reductase inhibitors are those agents which have beenmarketed, most preferred is fluvastatin and pitavastatin or, in eachcase, a pharmaceutically acceptable salt thereof.

The interruption of the enzymatic degradation of angiotensin I toangiotensin II with so-called ACE-inhibitors (also called angiotensinconverting enzyme inhibitors) is a successful variant for the regulationof blood pressure and thus also makes available a therapeutic method forthe treatment of congestive heart failure.

The class of ACE inhibitors comprises compounds having differingstructural features. For example, mention may be made of the compoundswhich are selected from the group consisting alacepril, benazepril,benazeprilat, captopril, ceronapril, cilazapril, delapril, enalapril,enaprilat, fosinopril, imidapril, lisinopril, moveltopril, perindopril,quinapril, ramipril, spirapril, temocapril, and trandolapril, or, ineach case, a pharmaceutically acceptable salt thereof.

Preferred ACE inhibitors are those agents that have been marketed, mostpreferred are benazepril and enalapril.

The class of CCBs essentially comprises dihydropyridines (DHPs) andnon-DHPs such as diltiazem-type and verapamil-type CCBs.

A CCB useful in said combination is preferably a DHP representativeselected from the group consisting of amlodipine, felodipine, ryosidine,isradipine, lacidipine, nicardipine, nifedipine, niguldipine,niludipine, nimodipine, nisoldipine, nitrendipine, and nicardipine, andis preferably a non-DHP representative selected from the groupconsisting of flunarizine, prenylamine, diltiazem, fendiline,gallopamil, mibefradil, anipamil, tiapamil and verapamil, and in eachcase, a pharmaceutically acceptable salt thereof. All these CCBs aretherapeutically used, e.g. as anti-hypertensive, anti-angina pectoris oranti-arrhythmic drugs.

Preferred CCBs comprise amlodipine, diltiazem, isradipine, nicardipine,nifedipine, nimodipine, nisoldipine, nitrendipine, and verapamil, or,e.g. dependent on the specific CCB, a pharmaceutically acceptable saltthereof. Especially preferred as DHP is amlodipine or a pharmaceuticallyacceptable salt, especially the besylate, thereof. An especiallypreferred representative of non-DHPs is verapamil or a pharmaceuticallyacceptable salt, especially the hydrochloride, thereof.

A preferred dual angiotensin converting enzyme/neutral endopetidase(ACE/NEP) inhibitor is, for example, omapatrilate (cf. EP 629627),fasidotril or fasidotrilate, or, if appropriable, a pharmaceuticallyacceptable salt thereof.

A preferred endothelin antagonist is, for example, bosentan (cf. EP526708 A), furthermore, tezosentan (cf. WO 96/19459), or in each case, apharmaceutically acceptable salt thereof.

Suitable renin inhibitors include compounds having different structuralfeatures. For example, mention may be made of compounds which areselected from the group consisting of ditekiren (chemical name:[1S-[1R*,2R*,4R*(1R*,2R*)]]-1-[(1,1-dimethylethoxy)carbonyl]-L-prolyI-L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alfa-methyl-L-histidinamide);terlakiren (chemical name:[R—(R*,S*)]-N-(4-morpholinylcarbonyl)-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2-hydroxy-3-(1-methylethoxy)-3-oxopropyl]-S-methyl-L-cysteineamide);and zankiren (chemical name:[1S-[1R[R*(R*)],2S*,3R*]]-N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl)-alfa-[[2-[[(4-methyl-1-piperazinyl)sulfonyl]methyl]-1-oxo-3-phenylpropyl]-amino]-4-thiazolepropanamide),preferably, in each case, the hydrochloride salt thereof, SPP630, SPP635and SPP800 as developed by Speedel.

Preferred renin inhibitor of the present invention include RO 66-1132and RO 66-1168 of formula (A) and (B)

respectively, or a pharmaceutically acceptable salt thereof.

In particular, the present invention relates to a renin inhibitor whichis a δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amide derivative of theformula (C)

wherein R₁ is halogen, C₁₋₆halogenalkyl, C₁₋₆alkoxy-C₁₋₆alkyloxy orC₁₋₆alkoxy-C₁₋₆alkyl; R₂ is halogen, C₁₋₄alkyl or C₁₋₄alkoxy; R₃ and R₄are independently branched C₃₋₆alkyl; and R₅ is cycloalkyl, C₁₋₆alkyl,C₁₋₆hydroxyalkyl, C₁₋₆alkoxy-C₁₋₆alkyl, C₁₋₆alkanoyloxy-C₁₋₆alkyl,C₁₋₆aminoalkyl, C₁₋₆alkylamino-C₁₋₆alkyl, C₁₋₆dialkylamino-C₁₋₆alkyl,C₁₋₆alkanoylamino-C₁₋₆alkyl, HO(O)C—C₁₋₆alkyl,C₁₋₆alkyl-O—(O)C—C₁₋₆alkyl, H₂N—C(O)—C₁₋₆alkyl,C₁₋₆alkyl-HN—C(O)—C₁₋₆alkyl or (C₁₋₆alkyl)₂N—C(O)—C₁₋₆alkyl; or apharmaceutically acceptable salt thereof.

As an alkyl, R₁ may be linear or branched and preferably comprise 1 to 6C atoms, especially 1 or 4 C atoms. Examples are methyl, ethyl, n- andi-propyl, n-, i- and t-butyl, pentyl and hexyl.

As a halogenalkyl, R₁ may be linear or branched and preferably comprise1 to 4 C atoms, especially 1 or 2 C atoms. Examples are fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

As an alkoxy, R₁ and R₂ may be linear or branched and preferablycomprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- andi-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.

As an alkoxyalkyl, R₁ may be linear or branched. The alkoxy grouppreferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkylgroup preferably comprises 1 to 4 C atoms. Examples are methoxymethyl,2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, 5-methoxypentyl,6-methoxyhexyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl,4-ethoxybutyl, 5-ethoxypentyl, 6-ethoxyhexyl, propyloxymethyl,butyloxymethyl, 2-propyloxyethyl and 2-butyloxyethyl.

As a C₁₋₆alkoxy-C₁₋₆alkyloxy, R₁ may be linear or branched. The alkoxygroup preferably comprises 1 to 4 and especially 1 or 2 C atoms, and thealkyloxy group preferably comprises 1 to 4 C atoms. Examples aremethoxymethyloxy, 2-methoxyethyloxy, 3-methoxypropyloxy,4-methoxybutyloxy, 5-methoxypentyloxy, 6-methoxyhexyloxy,ethoxymethyloxy, 2-ethoxyethyloxy, 3-ethoxypropyloxy, 4-ethoxybutyloxy,5-ethoxypentyloxy, 6-ethoxyhexyloxy, propyloxymethyloxy,butyloxymethyloxy, 2-propyloxyethyloxy and 2-butyloxyethyloxy.

In a preferred embodiment, R₁ is methoxy- or ethoxy-C₁₋₄alkyloxy, and R₂is preferably methoxy or ethoxy. Particularly preferred are compounds offormula (III), wherein R₁ is 3-methoxypropyloxy and R₂ is methoxy.

As a branched alkyl, R₃ and R₄ preferably comprise 3 to 6 C atoms.Examples are i-propyl, i- and t-butyl, and branched isomers of pentyland hexyl. In a preferred embodiment, R₃ and R₄ in compounds of formula(C) are in each case i-propyl.

As a cycloalkyl, R₅ may preferably comprise 3 to 8 ring-carbon atoms,3or 5 being especially preferred. Some examples are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. The cycloalkyl mayoptionally be substituted by one or more substituents, such as alkyl,halo, oxo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thiol,alkylthio, nitro, cyano, heterocyclyl and the like.

As an alkyl, R₅ may be linear or branched in the form of alkyl andpreferably comprise 1 to 6 C atoms. Examples of alkyl are listed hereinabove. Methyl, ethyl, n- and i-propyl, n-, i- and t-butyl are preferred.

As a C₁₋₆hydroxyalkyl, R₅ may be linear or branched and preferablycomprise 2 to 6 C atoms. Some examples are 2-hydroxyethyl,2-hydroxypropyl, 3-hydroxypropyl, 2-, 3- or 4-hydroxybutyl,hydroxypentyl and hydroxyhexyl.

As a C₁₋₆alkoxy-C₁₋₆alkyl, R₅ may be linear or branched. The alkoxygroup preferably comprises 1 to 4 C atoms and the alkyl group preferably2 to 4 C atoms. Some examples are 2-methoxyethyl, 2-methoxypropyl,3-methoxypropyl, 2-, 3 or 4-methoxybutyl, 2-ethoxyethyl, 2-ethoxypropyl,3-ethoxypropyl, and 2-, 3- or 4-ethoxybutyl.

As a C₁₋₆alkanoyloxy-C₁₋₆alkyl, R₅ may be linear or branched. Thealkanoyloxy group preferably comprises 1 to 4 C atoms and the alkylgroup preferably 2 to 4 C atoms. Some examples are formyloxymethyl,formyloxyethyl, acetyloxyethyl, propionyloxyethyl and butyroyloxyethyl.

As a C₁₋₆aminoalkyl, R₅ may be linear or branched and preferablycomprise 2 to 4 C atoms. Some examples are 2-aminoethyl, 2- or3-aminopropyl and 2-, 3- or 4-aminobutyl.

As C₁₋₆alkylamino-C₁₋₆alkyl and C₁₋₆dialkylamino-C₁₋₆alkyl, R₅ may belinear or branched. The alkylamino group preferably comprises C₁₋₄alkylgroups and the alkyl group has preferably, 2 to 4 C atoms. Some examplesare 2-methylaminoethyl, 2-dimethylaminoethyl, 2-ethylaminoethyl,2-ethylaminoethyl, 3-methylaminopropyl, 3-dimethylaminopropyl,4-methylaminobutyl and 4-dimethylaminobutyl.

As a HO(O)C—C₁₋₆alkyl, R₅ may be linear or branched and the alkyl grouppreferably comprises 2 to 4 C atoms. Some examples are carboxymethyl,carboxyethyl, carboxypropyl and carboxybutyl.

As a C₁₋₆alkyl-O—(O)C—C₁₋₆alkyl, R₅ may be linear or branched, and thealkyl groups preferably comprise, independently of one another 1 to 4 Catoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonylethyl,3-methoxycarbonylpropyl, 4-methoxy-carbonylbutyl, ethoxycarbonylmethyl,2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, and4-ethoxycarbonylbutyl.

As a H₂N—C(O)—C₁₋₆alkyl, R₅ may be linear or branched, and the alkylgroup preferably comprises 2 to 6 C atoms. Some examples arecarbamidomethyl, 2-carbamidoethyl, 2-carbamido-2,2-dimethylethyl, 2- or3-carbamidopropyl, 2-, 3- or 4-carbamidobutyl,3-carbamido-2-methylpropyl, 3-carbamido-1,2-dimethylpropyl,3-carbamido-3-ethylpropyl, 3-carbamido-2,2-dimethylpropyl, 2-, 3-, 4- or5-carbamidopentyl, 4-carbamido-3,3- or -2,2-dimethylbutyl. Preferably,R₅ is 2-carbamido-2,2-dimethylethyl.

Accordingly, preferred are δ-amino-γ-hydroxy-ω-aryl-alkanoic acid amidederivatives of formula (C) having the formula

wherein R₁ is 3-methoxypropyloxy; R₂ is methoxy; and R₃ and R₄ areisopropyl; or a pharmaceutically acceptable salt thereof; chemicallydefined as2(S),4(S),5(S),7(S)—N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(1-methylethyl)-4-hydroxy-5-amino-8-[4-methoxy-3-(3-methoxy-propoxy)phenyl]-octanamide,also known as, aliskiren.

The term “aliskiren”, if not defined specifically, is to be understoodboth as the free base and as a salt thereof, especially apharmaceutically acceptable salt thereof, most preferably ahemi-fumarate salt thereof.

A diuretic is, for example, a thiazide derivative selected from thegroup consisting of chlorothiazide, hydrochlorothiazide,methylclothiazide, and chlorothalidon. The most preferred ishydrochlorothiazide.

An ApoA-I mimic is, for example, D4F peptide, especially of formulaD-W-F-K-A-F-V-D-K-V-A-E-K-F-K-E-A-F

An anti-diabetic agents include insulin secretion enhancers which areactive ingredients that have the property to promote the secretion ofinsulin from pancreatic β-cells. Examples of insulin secretion enhancersare a biguanide derivative, for example, metformin or, if appropriate, apharmaceutically acceptable salt thereof, especially the hydrochloridethereof. Other insulin secretion enhancers include sulfonylureas (SU),especially those which promote the secretion of insulin from pancreaticβ-cells by transmitting signals of insulin secretion via SU receptors inthe cell membrane, including (but are not limited to) tolbutamide;chlorpropamide; tolazamide; acetohexamide;4-chloro-N-[(1-pyrolidinylamino)carbonyl]-benzensulfonamide(glycopyramide); glibenclamide (glyburide); gliclazide;1-butyl-3-metanilylurea; carbutamide; glibonuride; glipizide;gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide;glymidine; glypinamide; phenbutamide; and tolylcyclamide, orpharmaceutically acceptable salts thereof.

Insulin secretion enhancers furthermore include short-acting insulinsecretion enhancers, such as the phenylalanine derivative nateglinide[N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine] (cf. EP 196222and EP 526171) of the formula

and repaglinide[(S)-2-ethoxy-4-{2-[[3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl}benzoicacid]. Repaglinide is disclosed in EP 589874, EP 147850 A2, inparticular Example 11 on page 61, and EP 207331 A1. It can beadministered in the forth as it is marketed, e.g. under the trademarkNovoNorm™; calcium(2S)-2-benzyl-3-(cis-hexahydro-2-isoindolinlycarbonyl)-propionatedihydrate (mitiglinide—cf. EP 507534); furthermore representatives ofthe new generation of SUs such as glimepiride (cf. EP 31058); in free orpharmaceutically acceptable salt form. The term nateglinide likewisecomprises crystal modifications such as disclosed in EP 0526171 B1 orU.S. Pat. No. 5,488,510, respectively, the subject matter of which,especially with respect to the identification, manufacture andcharacterization of crystal modifications, is herewith incorporated byreference to this application, especially the subject matter of claims 8to 10 of said U.S. patent (referring to H-form crystal modification) aswell as the corresponding references to the B-type crystal modificationin EP 196222 B1 the subject matter of which, especially with respect tothe identification; manufacture and characterization of the B-formcrystal modification. Preferably, in the present invention, the B- orH-type, more preferably the H-type, is used. Nateglinide can beadministered in the form as it is marketed e.g. under the trademarkSTARLIX™.

Insulin secretion enhancers likewise include the long-acting insulinsecretion enhancer DPP-IV inhibitors, GLP-1 and GLP-1 agonists.

DPP-IV is responsible for inactivating GLP-1. More particularly, DPP-IVgenerates a GLP-1 receptor antagonist and thereby shortens thephysiological response to GLP-1. GLP-1 is a major stimulator ofpancreatic insulin secretion and has direct beneficial effects onglucose disposal.

The DPP-IV inhibitor can be peptidic or, preferably, non-peptidic.DPP-IV inhibitors are in each case generically and specificallydisclosed e.g. in WO 98/19998, DE 196 16 486 A1, WO 00/34241 and WO95/15309, in each case in particular in the compound claims and thefinal products of the working examples, the subject-matter of the finalproducts, the pharmaceutical preparations and the claims are herebyincorporated into the present application by reference to thesepublications. Preferred are those compounds that are specificallydisclosed in Example 3 of WO 98/19998 and Example 1 of WO 00/34241,respectively.

GLP-1 is a insulinotropic proteine which was described, e.g., by W. E.Schmidt et al. in Diabetologia, 28, 1985, 704-707 and in U.S. Pat. No.5,705,483.

The term “GLP-1 agonists” used herein means variants and analogs ofGLP-1(7-36)NH₂ which are disclosed in particular in U.S. Pat. No.5,120,712, U.S. Pat. No. 5,118,666, U.S. Pat. No. 5,512,549, WO 91/11457and by C. Orskov at al in J. Biol. Chem. 264 (1989) 12826. The term“GLP-1 agonists” comprises especially compounds like GLP-1(7-37), inwhich compound the carboxy-terminal amide functionality of Arg³⁶ isdisplaced with Gly at the 37^(th) position of the GLP-1(7-36)NH₂molecule and variants and analogs thereof including GLN⁹-GLP-1(7-37),D-GLN⁹-GLP-1(7-37), acetyl LYS⁹-GLP-1(7-37), LYS¹⁸-GLP-1(7-37) and, inparticular, GLP-1(7-37)GLP-1, VAL⁸-GLP-1(7-37), GLY⁸-GLP-1(7-37),THR⁸-GLP-1(7-37), MET⁸-GLP-1(7-37) and 4-imidazopropionyl-GLP-1. Specialpreference is also given to the GLP agonist analog exendin-4, describedby Greig et al in Diabetologia 1999, 42, 45-50.

An insulin sensitivity enhancer restores impaired insulin receptorfunction to reduce insulin resistance and consequently enhance theinsulin sensitivity.

An appropriate insulin sensitivity enhancer is, for example, anappropriate hypoglycemic thiazolidinedione derivative (glitazone).

An appropriate glitazone is, for example,(S)-((3,4-dihydro-2-(phenyl-methyl)-2H-1-benzopyran-6-yl)methyl-thiazolidine-2,4-dione(englitazone),5-{[4-(3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl)-phenyl]-methyl}-thiazolidine-2,4-dione(darglitazone),5-{[(4-(1-methyl-cyclohexyl)methoxy)-phenyl]methyl}-thiazolidine-2,4-dione(ciglitazone),5-{[4-(2-(1-indolyl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione(DRF2189),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxyl)]benzyl}-thiazolidine-2,4-dione(BM-13.1246), 5-(2-naphthylsulfonyl)-thiazolidine-2,4-dione (AY-31637),bis{4-[(2,4-dioxo-5-thiazolidinyl)methyl]phenyl}methane (YM268),5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-hydroxyethoxy]benzyl}-thiazolidine-2,4-dione(AD-5075),5-[4-(1-phenyl-1-cyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione(DN-108)5-{[4-(2-(2,3-dihydroindol-1-yl)ethoxy)phenyl]methyl}-thiazolidine-2,4-dione,5-[3-(4-chloro-phenyl])-2-propynyl]-5-phenylsulfonyl)thiazolidine-2,4-dione,5-[3-(4-chlorophenyl])-2-propynyl]-5-(4-fluorophenyl-sulfonyl)thiazolidine-2,4-dione,5-{[4-(2-(methyl-2-pyridinyl-amino)-ethyl)phenyl]methyl}thiazolidine-2,4-dione(rosiglitazone),5-{[4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl]-methyl}thiazolidine-2,4-dione(pioglitazone),5-{[4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)-phenyl]-methyl}-thiazolidine-2,4-dione(troglitazone),5-[6-(2-fluoro-benzyloxy)naphthalen-2-ylmethyl]-thiazolidine-2,4-dione(MCC555),5-{[2-(2-naphthyl)-benzoxazol-5-yl]-methyl}thiazolidine-2,4-dione(T-174) and5-(2,4-dioxothiazolidin-5-ylmethyl)-2-methoxy-N-(4-trifluoromethyl-benzyl)benzamide(KRP297). Preferred are pioglitazone, rosiglitazone and troglitazone.

Other anti-diabetic agents include, insulin signalling pathwaymodulators, like inhibitors of protein tyrosine phosphatases (PTPases),antidiabetic non-small molecule mimetic compounds and inhibitors ofglutamine-fructose-6-phosphate amidotransferase (GFAT); compoundsinfluencing a dysregulated hepatic glucose production, like inhibitorsof glucose-6-phosphatase (G6 Pase), inhibitors offructose-1,6-bisphosphatase (F-1,6-BPase), inhibitors of glycogenphosphorylase (GP), glucagon receptor antagonists and inhibitors ofphosphoenolpyruvate carboxykinase (PEPCK); pyruvate dehydrogenase kinase(PDHK) inhibitors; inhibitors of gastric emptying; insulin; inhibitorsof GSK-3; retinoid X receptor (RXR) agonists; agonists of Beta-3 AR;agonists of uncoupling proteins (UCPs); non-glitazone type PPARγagonists; dual PPARα/PPARγ agonists; antidiabetic vanadium containingcompounds; incretin hormones, like glucagon-like peptide-1 (GLP-1) andGLP-1 agonists; beta-cell imidazoline receptor antagonists; miglitol;and α₂-adrenergic antagonists; in which the active ingredients arepresent in each case in free form or in the form of a pharmaceuticallyacceptable salt.

An obesity-reducing agent includes lipase inhibitors such as orlistatand appetite suppressants such as sibutramine, phentermine.

An aldosteron receptor blocker includes spironolactone and eplerenone.

An endothelin receptor blocker includes bosentan, etc.

A CETP inhibitor refers to a compound that inhibits the cholesterylester transfer protein (CETP) mediated transport of various cholesterylesters and triglycerides from HDL to LDL and VLDL. Such CETP inhibitionactivity is readily determined by those skilled in the art according tostandard assays (e.g., U.S. Pat. No. 6,140,343). The CETP inhibitorsinclude those disclosed in U.S. Pat. No. 6,140,343 and U.S. Pat. No.6,197,786. CETP inhibitors disclosed in these patents include compounds,such as[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester, which is also known as torcetrapib. CETP inhibitorsare also described in U.S. Pat. No. 6,723,752, which includes a numberof CETP inhibitors including(2R)-3-{[3-(4-Chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methyl]-amino}-1,1,1-trifluoro-2-propanol.CETP inhibitors also include those described in U.S. patent applicationSer. No. 10/807,838 filed Mar. 23, 2004. U.S. Pat. No. 5,512,548discloses certain polypeptide derivatives having activity as CETPinhibitors, also certain CETP-inhibitory rosenonolactone derivatives andphosphate-containing analogs of cholesteryl ester are disclosed in J.Antibiot, 49(8): 815-816 (1996), and Bioorg. Med. Chem. Lett.;6:1951-1954 (1996), respectively. Furthermore, the CETP inhibitors alsoinclude those disclosed in WO2000/017165, WO2005/095409 andWO2005/097806.

A Na_K-ATPase inhibitor can be used to inhibit the Na and K exchangeacross the cell membranes. Such inhibitor can be for example digoxin.

A beta-adrenergic receptor blocker includes but is not limited to:esmolol especially the hydrochloride thereof; acebutolol, which may beprepared as disclosed in U.S. Pat. No. 3,857,952; alprenolol, which maybe prepared as disclosed in Netherlands Patent Application No.6,605,692; amosulalol, which may be prepared as disclosed in U.S. Pat.No. 4,217,305; arotinolol, which may be prepared as disclosed in U.S.Pat. No. 3,932,400; atenolol, which may be prepared as disclosed in U.S.Pat. No. 3,663,607 or 3,836,671; befunolol, which may be prepared asdisclosed in U.S. Pat. No. 3,853,923; betaxolol, which may be preparedas disclosed in U.S. Pat. No. 4,252,984; bevantolol, which may beprepared as disclosed in U.S. Pat. No. 3,857,981; bisoprolol, which maybe prepared as disclosed in U.S. Pat. No. 4,171,370; bopindolol, whichmay be prepared as disclosed in U.S. Pat. No. 4,340,541; bucumolol,which may be prepared as disclosed in U.S. Pat. No. 3,663,570;bufetolol, which may be prepared as disclosed in U.S. Pat. No.3,723,476; bufuralol, which may be prepared as disclosed in U.S. Pat.No. 3,929,836; bunitrolol, which may be prepared as disclosed in U.S.Pat. Nos. 3,940,489 and 3,961,071; buprandolol, which may be prepared asdisclosed in U.S. Pat. No. 3,309,406; butiridine hydrochloride, whichmay be prepared as disclosed in French Patent No. 1,390,056;butofilolol, which may be prepared as disclosed in U.S. Pat. No.4,252,825; carazolol, which may be prepared as disclosed in GermanPatent No. 2,240,599; carteolol, which may be prepared as disclosed inU.S. Pat. No. 3,910,924; Carvedilol, which may be prepared as disclosedin U.S. Pat. No. 4,503,067; celiprolol, which may be prepared asdisclosed in U.S. Pat. No. 4,034,009; cetamolol, which may be preparedas disclosed in U.S. Pat. No. 4,059,622; cloranolol which may beprepared as disclosed in German Patent No. 2,213,044; dilevalol, whichmay be prepared as disclosed in Clifton et al., Journal of MedicinalChemistry, 1982, 25, 670; epanolol, which may be prepared as disclosedin European Patent Publication Application No. 41, 491; indenolol, whichmay be prepared as disclosed in U.S. Pat. No. 4,045,482; labetalol,which may be prepared as disclosed in U.S. Pat. No. 4,012,444;levobunolol, which may be prepared as disclosed in U.S. Pat. No.4,463,176; mepindolol; which may be prepared as disclosed in Seeman etal., Helv. Chim. Acta, 1971, 54, 241; metipranolol, which may beprepared as disclosed in Czechoslovakian Patent Application No. 128,471;metoprolol, which may be prepared as disclosed in U.S. Pat. No.3,873,600; moprolol, which may be prepared as disclosed in U.S. Pat. No.3,501,7691; nadolol, which may be prepared as disclosed in U.S. Pat. No.3,935,267; nadoxolol, which may be prepared as disclosed in U.S. Pat.No. 3,819,702; nebivalol, which may be prepared as disclosed in U.S.Pat. No. 4,654,362; nipradilol, which may be prepared as disclosed inU.S. Pat. No. 4,394,382; oxprenolol, which may be prepared as disclosedin British Patent No. 1,077,603; perbutolol, which may be prepared asdisclosed in U.S. Pat. No. 3,551,493; pindolol, which may be prepared asdisclosed in Swiss Patent Nos. 469,002 and 472,404; practolol, which maybe prepared as disclosed in U.S. Pat. No. 3,408,387; pronethalol, whichmay be prepared as disclosed in British Patent No. 909,357; propranolol,which may be prepared as disclosed in U.S. Pat. Nos. 3,337,628 and3,520,919; sotalol, which may be prepared as disclosed in Uloth et al.,Journal of Medicinal Chemistry, 1966, 9, 88; sufinalol, which may beprepared as disclosed in German Patent No. 2,728,641; talindol, whichmay be prepared as disclosed in U.S. Pat. Nos. 3,935,259 and 4,038,313;tertatolol, which may be prepared as disclosed in U.S. Pat. No.3,960,891; tilisolol, which may be prepared as disclosed in U.S. Pat.No. 4,129,565; timolol, which may be prepared as disclosed in U.S. Pat.No. 3,655,663; toliprolol, which may be prepared as disclosed in U.S.Pat. No. 3,432,545; and xibenolol, which may be prepared as disclosed inU.S. Pat. No. 4,018,824.

An alpha-adrenergic receptor blocker includes but is not limited to:amosulalol, which may be prepared as disclosed in U.S. Pat. No.4,217,307; arotinolol, which may be prepared as disclosed in U.S. Pat.No. 3,932,400; dapiprazole, which may be prepared as disclosed in U.S.Pat. No. 4,252,721; doxazosin, which may be prepared as disclosed inU.S. Pat. No. 4,188,390; fenspiride, which may be prepared as disclosedin U.S. Pat. No. 3,399,192; indoramin, which may be prepared asdisclosed in U.S. Pat. No. 3,527,761; labetolol, which may be preparedas disclosed above; naftopidil, which may be prepared as disclosed inU.S. Pat. No. 3,997,666; nicergoline, which may be prepared as disclosedin U.S. Pat. No. 3,228,943; prazosin, which may be prepared as disclosedin U.S. Pat. No. 3,511,836; tamsulosin, which may be prepared asdisclosed in U.S. Pat. No. 4,703,063; tolazoline, which may be preparedas disclosed in U.S. Pat. No. 2,161,938; trimazosin, which may beprepared as disclosed in U.S. Pat. No. 3,669,968; and yohimbine, whichmay be isolated from natural sources according to methods well known tothose skilled in the art.

The natriuretic peptides constitute a family of peptides that includethe atrial (ANP), brain-derived (BNP) and C-type natriuretic (CNP)peptides. The natriuretic peptides effect vasodilation, natriuresis,diuresis, decreased aldosterone release, decreased cell growth, andinhibition of the sympathetic nervous system and therenin-angiotensin-aldosterone system indicating their involvement in theregulation of blood pressure and of sodium and water balance. Neutralendopeptidase 24, 11 (NEP) inhibitors impede degradation of natriureticpeptides and elicit pharmacological actions potentially beneficial inthe management of several cardiovascular disorders. A NEP inhibitoruseful in the said combination is an agent selected from the grouprepresented by candoxatril, sinorphan, SCH 34826 and SCH 42495.

An inotropic agent is selected from the group consisting of: digoxin,digitoxin, digitalis, dobutamine, dopamine, epinephrine, milrinone,aminone and norepinephrine, etc.

A compound of the present invention may be administered eithersimultaneously, before or after the other active ingredient, eitherseparately by the same or different route of administration or togetherin the same pharmaceutical formulation.

Furthermore, the combinations as described above can be administered toa subject via simultaneous, separate or sequential administration (use).Simultaneous administration (use), can take place in the form of onefixed combination with two or three or more active ingredients, or bysimultaneously administering two or three or more compounds that areformulated independently. Sequential administration(use) preferablymeans administration of one (or more) compounds or active ingredients ofa combination at one time point, other compounds or active ingredientsat a different time point, that is, in a chronically staggered manner,preferably such that the combination shows more efficiency than thesingle compounds administered independently (especially showingsynergism). Separate administration (use) preferably meansadministration of the compounds or active ingredients of the combinationindependently of each other at different time points, preferably meaningthat two, or three or more compounds are administered such that nooverlap of measurable blood levels of both compounds are present in anoverlapping manner (at the same time).

Also combinations of two or three or more of sequential, separate andsimultaneous administrations are possible, preferably such that thecombination compound-drugs show a joint therapeutic effect that exceedsthe effect found when the combination compound drugs are usedindependently at time intervals so large that no mutual effect on theirtherapeutic efficiency can be found, a synergistic effect beingespecially preferred.

Alternatively, the pharmaceutical compositions contain a therapeuticallyeffective amount of a compound of the invention as defined above, eitheralone or in a combination with one or more therapeutic agents, e.g.,each at an effective therapeutic dose as reported in the art, selectedfrom the group consisting of an antiestrogen; an anti-androgen; agonadorelin agonist; a topoisomerase I inhibitor; a topoisomerase IIinhibitor; a microtubule active agent; an alkylating agent; ananti-neoplastic anti-metabolite; a platin compound; a compoundtargeting/decreasing a protein or lipid kinase activity or a protein orlipid phosphatase activity, a anti-angiogenic compound; a compound whichinduces cell differentiation processes; monoclonal antibodies; acyclooxygenase inhibitor; a bisphosphonate; a heparanase inhibitor; abiological response modifier; an inhibitor of Ras oncogenic isoforms; atelomerase inhibitor; a protease inhibitor, a matrix metalloproteinaseinhibitor, a Methionine aminopeptidase inhibitor; a proteasomeinhibitor; agents which target, decrease or inhibit the activity ofFlt-3; an HSP90 inhibitor; antiproliferative antibodies; an HDACinhibitor; a compound which targets, decreases or inhibits theactivity/function of serine/theronine mTOR kinase; a somatostatinreceptor antagonist; an anti-leukemic compound; tumor cell damagingapproaches; an EDG binder; a ribonucleotide reductase inhibitor; anS-adenosylmethionine decarboxylase inhibitor; a monoclonal antibody ofVEGF or VEGFR; photodynamic therapy; an Angiostatic steroid; an implantcontaining corticosteroids; an AT1 receptor antagonist; and an ACEinhibitor.

Additionally, the present invention provides:

-   -   a pharmaceutical composition or combination of the present        invention for use as a medicament;    -   the use of a pharmaceutical composition or combination of the        present invention for the delay of progression and/or treatment        of a disorder or disease mediated by aldosterone synthase, or        responsive to inhibition of aldosterone synthase, or        characterized by abnormal activity or expression of aldosterone        synthase.    -   the use of a pharmaceutical composition or combination of the        present invention for the delay of progression and/or treatment        of a disorder or disease mediated by aromatase, or responsive to        inhibition of aromatase, or characterized by abnormal activity        or expression of aromatase.    -   the use of a pharmaceutical Composition or combination of the        present invention for the delay of progression and/or treatment        of a disorder or disease selected from hypokalemia,        hypertension, congestive heart failure, atrial fibrillation,        renal failure, in particular, chronic renal failure, restenosis;        atherosclerosis, syndrome X, obesity, nephropathy,        post-Myocardial infarction, coronary heart diseases, increased        formation of collagen, fibrosis such as cardiac or myocardiac        fibrosis and remodeling following hypertension and endothelial        dysfunction.    -   the use of a pharmaceutical composition or combination of the        present invention for the delay of progression and/or treatment        of a disorder or disease selected from gynecomastia,        osteoporosis, prostate cancer, endometriosis, uterine fibroids,        dysfunctional uterine bleeding, endometrial hyperplasia,        polycystic ovarian disease, infertility, fibrocystic breast        disease, breast cancer and fibrocystic mastopathy.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredients for asubject of about 50-70 kg, preferably about 5-500 mg of activeingredients. The therapeutically effective dosage of a compound, thepharmaceutical composition, or the combinations thereof, is dependent onthe species of the subject, the body weight, age and individualcondition, the disorder or disease or the severity thereof beingtreated. A physician, clinician or veterinarian of ordinary skill canreadily determine the effective amount of each of the active ingredientsnecessary to prevent, treat or inhibit the progress of the disorder ordisease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats; dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., preferably aqueous solutions, and in vivo either enterally,parenterally, advantageously intravenously, e.g., as a suspension or inaqueous solution. The dosage in vitro may range between about 10⁻³ molarand 10⁻⁹ molar concentrations. A therapeutically effective amount invivo may range depending on the route of administration, between about0.1-500 mg/kg, preferably between about 1-100 mg/kg.

The activities of a compound according to the present invention can beassessed by the following in vitro & in vivo methods well-described inthe art. See Fieber, A et al. (2005), “Aldosterone Synthase InhibitorAmeliorates Angiotensin II-Induced Organ Damage,” Circulation,111:30874094; see also Stresser D M, Turner S D, McNamara J, et al(2000), “A high-throughput screen to identify inhibitors of aromatase(CYP19),” Anal Biochem; 284:427-30. All the references cited herein areincorporated by reference in their entirety.

In particular, the aldosterone synthase and aromatase inhibitoryactivities in vitro can be determined by the following assays.

Human adrenocortical carcinoma NCI-H295R cell line is obtained fromAmerican Type Culture Collection (Manassas, Va.).Insulin/transferrin/selenium (ITS)-A supplement (100×), DMEM/F-12,antibiotic/antimycotic (100×), and fetal calf serum (FCS) are purchasedfrom Gibco (Grand Island, N.Y.). Anti-mouse PVT scintillation proximityassay (SPA) beads and NBS 96-well plates are obtained from Amersham(Piscataway, N.J.) and Corning (Acton, Mass.), respectively. Solid black96-well flat bottom plates are purchased from Costar (Corning, N.Y.).Aldosterone and angiotensin (Ang II) are purchased from Sigma (St.Louis, Mo.). D-[1,2,6,7-³H(N)]aldosterone was acquired from PerkinElmer(Boston, Mass.). Nu-serum was a product of BD Biosciences (FranklinLakes, N.J.). The NADPH regenerating system, dibenzylfluorescein (DBF),and human aromatase Supersomes® are obtained from Gentest (Woburn,Mass.).

For in vitro measurement of aldosterone activity, human adrenocorticalcarcinoma NCI-H295R cells are seeded in NBS 96-well plates at a densityof 25,000 cells/well in 100 μl of a growth medium containing DMEM/F12supplemented with 10% FCS, 2.5% Nu-serum, 1 μg ITS/ml, and 1×antibiotic/antimycotic. The medium is changed after culturing for 3 daysat 37° C. under an atmosphere of 5% CO₂/95% air. On the following day,cells are rinsed with 100 μl of DMEM/F12 and incubated with 100 μl oftreatment medium containing 1 μM Ang II and a compound at differentconcentrations in quadruplicate wells at 37° C. for 24 hr. At the end ofincubation, 50 μl of medium is withdrawn from each well for measurementof aldosterone production by an RIA using mouse anti-aldosteronemonoclonal antibodies.

Measurement of aldosterone activity can also be performed using a96-well plate format. Each test sample is incubated with 0.02 μCi ofD-[1,2,6,7-³H(N)]aldosterone and 0.3 μg of anti-aldosterone antibody inphosphate-buffered saline (PBS) containing 0.1% Triton X-100, 0.1%bovine serum albumin, and 12% glycerol in a total volume of 200 μl atroom temperature for 1 hr. Anti-mouse PVT SPA beads (50 μl) are thenadded to each well and incubated overnight at room temperature prior tocounting in a Microbeta plate counter. The amount of aldosterone in eachsample is calculated by comparing with a standard curve generated usingknown quantities of the hormone.

To measure aromatase activity, the human aromatase assay is performed in96-well flat bottom plates according to a published protocol (Stresseret al, 2000) with minor modifications. Briefly, 10 μl of an NADPHregenerating system containing 2.6 mM NADP⁺, 6.6 mM glucose 6-phosphate,6.6 mM MgCl₂, and 0.8 U/ml glucose-6-phosphate dehydrogenase in 50 mMpotassium phosphate, pH 7.4, is pre-incubated with the test compound ata desired concentration at 30° C. for 10 min in a total volume of 100μl. Afterwards, 4 pmol of human aromatase, 20 μg of control microsomalprotein, and 4 μM DBF in 100 μl of 50 mM potassium phosphate, pH 7.4, isadded to each well and incubated at 30° C. for 90 min. The reaction isterminated by the addition of 75 μl of 2 N NaOH to each well. After 2hr, the product, fluorescein, is measured by a fluorimeter usingexcitation and emission wavelengths of 485 and 538 nm, respectively.

Full concentration-response curves of the test compound are performed atleast 3 times. The IC₅₀ values are derived using a non-linear leastsquares curve-fitting program from Microsoft XLfit.

The in vivo inhibitory activities for aldosterone synthase and aromatasecan be determined by the following assays.

Test compounds (i.e., potential aldosterone synthase inhibitors) areprofiled in vivo in a conscious rat model of acute secondaryhyperaldosteronism. Wild-type rats are instrumented with chronicallyindwelling arterial and venous cannulas, which are exteriorized througha tether/swivel system. The ambulatory rats are housed in specializedcages to allow blood sampling and parenteral drug, administrationwithout disturbing the animals. Angiotensin II is continuously infusedintravenously at a level sufficient to elevate plasma aldosteroneconcentration (PAC) by ˜200-fold to 1-5 nM. This PAC increase issustained at a stable level for at least 8-9 hours. Test compounds areadministered p.o. (via oral gavage) or parenterally (via the arterialcatheter) after one hour of angiotensin II infusion at a time when PAChas increased to a steady-state level. Arterial blood samples arecollected before and at various times (up to 24 hours) after test agentadministration for later determination of PAC and concentration of testagent. From these measurements, various parameters can be derived,e.g., 1) onset and duration of PAC reduction by the test agent 2)pharmacokinetic parameters of the test agent such as half-life,clearance, volume of distribution, and oral biovailability, 3) dose/PACresponse, dose/test-agent concentration, and test-agentconcentration/PAC response relationships, and 4) dose and concentrationpotencies and efficacy of the test agent. A successful test compounddecreases PAC in a dose- and time-dependent fashion in the dose range ofabout 0.01 to about 10 mg/kg i.a. or p.o.

TABLE 1 Inhibitory Activities of the Compounds % inhibition cellular ofaroma- aldosterone tase @ Compound IC₅₀ (nM) 10000 nM4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol- >1000 965-yl)-3-methylbenzonitrile, enantiomer A4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol- 7 965-yl)-3-methylbenzonitrile, enantiomer B5-(2-chloro-4-cyanophenyl)-6,7-dihydro- >>1000 985H-pyrrolo[1,2-c]imidazole-5-carboxylic acid(4-methoxybenzyl)methylamide, enantiomer A5-(2-chloro-4-cyanophenyl)-6,7-dihydro- 8 975H-pyrrolo[1,2-c]imidazole-5-carboxylic acid(4-methoxybenzyl)methylamide, enantiomer B4′-fluoro-6-(6,7,8,9-tetrahydro-5H- 2 97imidazo[1,5-a]azepin-5-yl)biphenyl-3- carbonitrile, enantiomer A4′-fluoro-6-(6,7,8,9-tetrahydro-5H- 50 70imidazo[1,5-a]azepin-5-yl)biphenyl-3- carbonitrile, enantiomer B5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro- 6 1005H-pyrrolo[1,2-c]imidazole-5-carboxylic acid butyl ester5-(2-Chloro-4-cyanophenyl)-6,7-dihydro- 45 965H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester5-(4-Cyano-2-methoxyphenyl)-6,7- 57 85dihydro-5H-pyrrolo[1,2-c]imidazole-5- carboxylic acid (4-fluorobenzyl)methylamide 5-(4-Cyano-2,5-dimethoxyphenyl)-6,7- 113 98dihydro-5H-pyrrolo[1,2-c]imidazole-5- carboxylic acid methyl ester3-Chloro-4-[5-(morpholino-4-carbonyl)- 3576,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5- yl]benzonitrile4-(6,7-Dihydro-5H-pyrrolo[1,2- 18 100c]imidazol-5-yl)-3-methoxybenzonitrile3-Amino-4-(6,7-dihydro-5H-pyrrolo[1,2- 90 100c]imidazol-5-yl)benzonitrile 5-(4-Cyano-2-trifluoromethylphenyl)-6,7-244 dihydro-5H-pyrrolo[1,2-c]imidazole-5- carboxylic acid methyl ester5-(3-fluoro-4-methoxyphenyl)-6,7- 159 100dihydro-5H-pyrrolo[1,2-c]imidazole5-(2-Chloro-4-cyanophenyl)-6,7-dihydro- >>1000 915H-pyrrolo[1,2-c]imidazole-5-carboxylic acid 4-fluorobenzyl ester,enantiomer A 5-(2-Chloro-4-cyanophenyl)-6,7-dihydro- 2 985H-pyrrolo[1,2-c]imidazole-5-carboxylic acid 4-fluorobenzyl ester,enantiomer B 3-Chloro-4-[5-(piperidine-1-carbonyl)- 135 986,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5- yl]-benzonitrile5-(4-Cyano-2-trifluoromethoxyphenyl)- 2 996,7-dihydro-5H-pyrrolo[1,2-c]imidazole- 5-carboxylic acid methyl ester5-(4-Cyano-2-methoxyphenyl)-6,7- 5 96dihydro-5H-pyrrolo[1,2-c]imidazole-5- carboxylic acid 2-isopropoxyethylester 4-(6,7-Dihydro-5H-pyrrolo[1,2- 31 95c]imidazol-5-yl)-3-vinylbenzonitrile 4-(6,7-Dihydro-5H-pyrrolo[1,2- 3 95c]imidazol-5-yl)-2-methylbenzonitrile 4-(6,7-Dihydro-5H-pyrrolo[1,2- 597 c]imidazol-5-yl)-2-methoxybenzonitrile 4-(6,7-Dihydro-5H-pyrrolo[1,2-8 100 c]imidazol-5-yl)-2-vinylbenzonitrile3-Fluoro-4-(7-methylene-6,7-dihydro-5H- 4 95pyrrolo[1,2-c]imidazol-5-yl)benzonitrile5′-[2-fluoro-4-cyano-phenyl]-5′,6′- 11 99dihydrospiro[cyclopropane-1,7′- pyrrolo[1,2-c]imidazole]5-(5-Fluorobiphenyl-2-yl)-5,6,7,8- 57 98tetrahydroimidazo[1,5-a]pyridine 5-(4-Fluoro-2-thiophen-3-yl-phenyl)- 9388 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine 6-(5-Methyl-5,6,7,8- 270tetrahydroimidazo[1,5-a]pyridin-5- yl)biphenyl-3-carbonitrile3-Methoxy-4-(5,6,7,8-tetrahydro- 270 100imidazo[1,5-a]pyridin-5-yl)benzonitrilecis-3-Fluoro-4-[7-(4-fluoro-benzyl)- 7 1005,6,7,8-tetrahydro-imidazo[1,5-a]pyridin- 5-yl]benzonitriletrans-3-Methoxy-4-[7-(4-fluorobenzyl)- 83 1005,6,7,8-tetrahydroimidazo[1,5-a]pyridin- 5-yl]benzonitrile4′-Fluoro-6-(9-methyl-6,7,8,9-tetrahydro- 2 915H-imidazo[1,5-a]azepin-5-yl)biphenyl- 3-carbonitrile5-(2-Bromo-4-fluorophenyl)-6,7,8,9- 65 92tetrahydro-5H-imidazo[1,5-a]azepine4′-Fluoro-6-(9-methyl-6,7,8,9-tetrahydro- 4 985H-imidazo[1,5-a]azepin-5-yl)biphenyl- 3-carbonitrile, isomer A4′-Fluoro-6-(9-methyl-6,7,8,9-tetrahydro- 2075H-imidazo[1,5-a]azepin-5-yl)biphenyl- 3-carbonitrile, isomer B4′-Fluoro-6-(9-methyl-6,7,8,9-tetrahydro- 16 815H-imidazo[1,5-a]azepin-5-yl)biphenyl- 3-carbonitrile, isomer C4′-Fluoro-6-(9-methyl-6,7,8,9-tetrahydro- 7275H-imidazo[1,5-a]azepin-5-yl)biphenyl- 3-carbonitrile, isomer D2-Bromo-4-(6,7,8,9-tetrahydro-5H- 23 100imidazo[1,5-a]azepin-5-yl)benzonitrile3-Pyridin-3-yl-4-(6,7,8,9-tetrahydro-5H- 35 97imidazo[1,5-a]azepin-5-yl)benzonitrile 4-(5-Allyl-6,7,8,9-tetrahydro-5H-32 97 imidazo[1,5-a]azepin-5-yl)-3- bromobenzonitrile3-Chloro-(5-ethyl-6,7,8,9-tetrahydro-5H- 217 91imidazo[1,5-a]azepin-5-yl)benzonitrile3-(3,5-Dimethylisoxazol-4-yl)-4-(6,7,8,9- 40 59tetrahydro-5H-imidazo[1,5-a]azepin-5- yl)benzonitrile3-Chloro-4-(6,7,8,9-tetrahydro-5H- 48 100imidazo[1,5-a]azepin-5-yl)benzonitrile 3′-Methylene-2′,3′,6,7,8,9- 11100 hexahydrospiro[imidazo[1,5-a]azepine- 5,1′-indene]-5′-carbonitrileAbbreviations DCM: dichloromethane DIBAL:diisobutylaluminum hydrideDMAP: N,N-dimethylaminopyridine DME: dimethoxyethane DMF:N,N-dimethylformamide DMSO: dimethylsulfoxide ESI: electrosprayionization h: hours HPLC: high pressure liquid chromatography HRMS: highresolution mass spectrometry IPA: iso-propyl alcohol IR: infraredspectroscopy KHMDS: Potassium hexamethyldisilazide LAH: lithium aluminumhydride LCMS: liquid chromatography/mass spectrometry LDA: lithiumdiisoproylamide LHMDS: lithium hexamethyldisilazide min: minutes MS:mass spectrometry NBS: N-bromosuccinimide NMR: nuclear magneticresonance PS—PPh₃—Pd(0): polymer supported palladium triphenylphosphinecomplex TBSCl: tert-butyldimethylsilyl chloride TFA: trifluoroaceticacid THF: tetrahydrofuran TMEDA: tetramethylethylenediamine TBS:tert-butyl dimethylsilyl TMSCl: trimethylsilyl chloride TLC: thin layerchromatography Tr: trityl t_(r): retention time TMEDA:tetramethylethylene diamine

EXAMPLES

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centrigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art. The compoundsin the following examples have been found to have IC₅₀ values in therange of about 0.1 nM to about 10,000 nM for both aldosterone synthaseand aromatase.

Example 1 Benzyl Bromides A. 4-Bromomethyl-3-chlorobenzonitrile (cas#21924-83-4)

3-Chloro-4-methylbenzonitrile (2.34 g, 15.4 mmol), NBS (3.0 g, 16.9mmol) and benzoyl peroxide (0.37 g, 1.54 mmol) are taken up in carbontetrachloride (50 mL, 0.3M) and refluxed until the reaction is judgedcomplete by TLC. The mixture is then allowed to cool to room temperatureand is filtered. The filtrate is concentrated and purified via flashcolumn chromatography (0-5% EtOAc/hexanes) to give4-bromomethyl-3-chlorobenzonitrile as a white solid. HRMS (ESI) m/z229.9133 (229.9193 calcd for C₈H₆ClBrN, M+H).

Similarly prepared are the following compounds from the correspondingtoluenes:

-   4-Bromomethyl-3-fluorobenzonitrile (cas #105942-09-4)-   4-Bromomethyl-2-bromobenzonitrile (cas #89892-38-6)-   4-Bromomethyl-3-methoxybenzonitrile (cas #104436-60-4)-   4-Bromomethyl-3-nitrobenzonitrile (cas #223512-70-7)-   3-Bromo-4-bromomethylbenzoic acid methyl ester (cas #78946-25-5)

B. 4-Bromomethyl-3-trifluoromethylbenzonitrile

4-Methyl-3-trifluoromethylbenzonitrile is brominated with NBS accordingto Example 1A to give 4-bromomethyl-3-trifluoromethylbenzonitrile. ¹HNMR (400 MHz, CDCl₃) δ (ppm) 7.94 (s, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.76(d, J=8.1 Hz, 1H), 4.63 (s, 2H).

C. 4-Bromomethyl-3-trifluoromethoxybenzonitrile

To a mixture of CuBr₂ (25.5 g, 114 mmol) in CH₃CN (500 mL) at 0° C. isadded t-butyl nitrite (17.7 mL, 148 mmol). Then4-amino-3-trifluoromethoxybenzonitrile (20.0 g, 99.0 mmol) is added in 4portions over a 10 min period. The mixture is allowed to warm to roomtemperature and stir overnight. The solvent is removed and the residueis partitioned between Et₂O and 1M HCl. The aqueous phase is furtherextracted with Et₂O and the combined organic layers are dried (Na₂SO₄)and concentrated. Solid residue is then triturated with hexanes to give4-Bromo-3-trifluoromethoxybenzonitrile as a yellow crystalline solid. ¹HNMR, (400 MHz, CDCl₃) δ (ppm) 7.47 (dd, J=8.0, 2.0 Hz, 1H), 7.59 (m,1H), 7.80 (d, J=8.0 Hz, 1H).

A mixture of 4-bromo-3-trifluoromethoxybenzonitrile (10.0 g, 37.6 mmol),K₂CO₃ (15.6 g, 113 mmol), trimethylboroxine (5.5 mL, 39.5 mmol) and DMF(150 mL) is degassed for 10 min with nitrogen before Pd(PPh₃)₄ (4.34 g,3.76 mmol) is added. The mixture is then sealed and heated to 120° C.for 14 h. The mixture is then concentrated and then partitioned betweenEt₂O and 50% brine solution. The aqueous phase is further extracted withEt₂O and the combined organic layers are dried (Na₂SO₄) andconcentrated. The residue is purified via flash chromatography (10%EtOAc/hexanes) to give 4-methyl-3-trifluoromethoxybenzonitrile. H NMR(400 MHz, CDCl₃) δ (ppm) 2.40 (s, 3H), 7.40 (d, J=7.7 Hz, 1H), 7.50 (s,1H), 7.51 (dd, J=7.7, 1.5 Hz, 1H). MS (ESI) m/z 202.1.

4-Methyl-3-Trifluoromethoxybenzonitrile is brominated with NBS accordingto Example 1A to give 4-bromomethyl-3-trifluoromethoxybenzonitrile. ¹HNMR (400 MHz, CDCl₃) δ (ppm) 4.51 (s, 2H), 7.55 (br s, 1H), 7.59 (d,J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H).

D. 4-Bromomethyl-2,5-dimethoxybenzonitrile

By analogy to steps outlined in J. Med. Chem. 1976, 19(12), 1400-1404.2,5-dimethoxy-4-methylbenzaldehyde (14.8 g, 82.2 mmol) is dissolved inpyridine (300 mL) and to it, is added hydroxylamine hydrochloride (6.8g, 98.6 mmol). The suspension is heated at 105° C. for 2 h. Aceticanhydride (15.5 mL, 164 mmol) is then added to the reaction and stirringis continued for another 2 h. The solution is evaporated to dryness andpartitioned between EtOAc and saturated aqueous NaHCO₃. The organicfraction is dried (Na₂SO₄) and evaporated to give a yellow solid whichis taken up in hexanes and filtered to give2,5-dimethoxy-4-methylbenzonitrile as a white solid. (cas #51267-09-5)MS (ESI) m/z 178.2 (M+H).

2,5-Dimethoxy-4-methylbenzonitrile (4.06 g, 21.5 mmol) is brominateswith NBS according to Example 1A to give4-bromomethyl-2,5-dimethoxybenzonitrile. ¹H NMR (400 MHz, CDCl₃) δ (ppm)6.95 (s, 1H), 6.91 (s, 1H), 4.43 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H).

Similarly prepared is the following:

4-Bromomethyl-3-bromobenzonitrile (cas #89892-39-7). ¹H NMR (400 MHz,CDCl₃) δ (ppm) 7.87 (d, 1H, J=1.2 Hz), 7.60 (dd, 1H, J=7.6, 1.2 Hz),7.57 (d, 1H, J=7.6 Hz), 4.58 (s, 2H).

D. 2-Bromomethyl-4′-fluorobiphenyl (cas #791078-01-8)

To a mixture of 4-fluorophenylboronic acid (2.5 g, 13.4 mmol),2-bromobenzyl alcohol (2.81 g, 20.1 mmol) and Pd(PPh₃)₄ (0.25 g, 0.216mmol) in DME (20 mL) is added an aqueous solution of Na₂CO₃ (11.5 mL,2.7 M, 31 mmol). The mixture is heated to 115° C. in sealed vesselovernight. The reaction is allowed to cool to room temperature and isdiluted with EtOAc and water. The aqueous layer is extracted furtherwith EtOAc (2×). The combined organic layers are washed with water,saturated NH₄Cl, brine and dried over Na₂SO₄. After concentration, theresulting residue is purified by flash chromatography (hexane/CH₂Cl₂) togive (4′-fluorobiphenyl-2-yl)-methanol as oil. (cas #773871-75-3) ¹H NMR(400 MHz, CDCl₃) δ (ppm) 7.46-7.43 (m, 1H), 7.32-7.22 (m, 4H), 7.18-7.16(m, 1H), 7.04-6.99 (m, 2H), 4.48 (d, J=5.5 Hz, 2H), 1.68 (br s, 1H).

To a solution of (4′-fluorobiphenyl-2-yl)-methanol (2.58 g, 12.8 mmol)in CH₂Cl₂ (100 mL), carbon tetrabromide (7.40 g, 22.3 mmol) is added.The solution is cooled to 0° C. and then triphenylphosphine (7.53 g,28.7 mmol) is added portionwise. The reaction is stirred at 0° C. for1.5 h and then at room temperature for 90 h before the solvent isremoved. The resulting residue is partitioned between Et₂O and water andthen filtered. The layers are separated and the aqueous layer isextracted with Et₂O. The combined organic layers are washed with water,brine and dried over Na₂SO₄. After concentration, the residue ispurified by flash chromatography (hexane) to give2-bromomethyl-4′-fluorobiphenyl as an oil. (an alternative preparationappears in J. Med. Chem. 2004, 47(22), 5441) ¹H NMR (400 MHz, CDCl₃) δ7.53-7.50 (m, 1H), 7.43-7.31 (m, 4H), 7.24-7.21 (m, 1H), 7.15-6.80 (m,2H), 4.42 (s, 2H).

E. Bromo-(3-fluoro-4-methoxyphenyl)acetic acid methyl ester

(3-Fluoro-4-methoxyphenyl)acetic acid (5.0 g, 27.1 mmol) is dissolved inMeOH (100 mL). To it is added concentrated H₂SO₄ (5 mL) and the solutionis warmed to reflux for 2 h. At that point, the solution is evaporatedto dryness and taken up in EtOAc. The solution is washed with saturatedaqueous NaHCO₃, dried (Na₂SO₄) and evaporated to give(3-fluoro-4-methoxyphenyl)acetic acid methyl ester (cas#588-14-7) as ayellow oil. MS (ESI) m/z 199.3 (M+H).

The (3-fluoro-4-methoxyphenyl)acetic acid methyl ester (5.16 g, 26.0mmol) is dissolved in carbon tetrachloride (300 mL) along with NBS (5.56g, 31.3 mmol) and benzoyl peroxide (0.63 g, 2.60 mmol) and refluxed for2 h. The solution is then allowed to cool to room temperature and isfiltered. The filtrate is evaporated and the residue purified via flashcolumn chromatography (EtOAc/hexanes 5:95→EtOAc/hexanes 2:8) to givebromo-(3-fluoro-4-methoxyphenyl)acetic acid methyl ester as a yellowoil. ¹H NMR (CDCl₃) δ 7.37 (d, J=12 Hz, 1H), 7.26-7.23 (m, 1H), 6.93 (t,J=8 Hz, 1H), 5.31 (s, 1H), 3.91 (s, 3H), 3.81 s, 3H).

Example 2 Substituted imidazole Intermediates A.1-Trityl-4-carboxaldehyde-1H-imidazole (cas #33016-47-6)

According to procedure outlined in J. Med. Chem. 2002, 45(1), 177, toimidazole-4-carboxaldehyde (15.0 g, 156.2 mmol) in DMF (300 mL) is addedtriethylamine (43.8 ml, 312 mmol) followed by trityl chloride (44.4 g,159.0 mmol). The reaction mixture is stirred at ambient temperature for18 h before the solvent is removed in vacuo. The resulting solid isdissolved in dichloromethane and washed with sodium bicarbonate andwater. The organic phase is concentrated in vacuo to give the desiredmaterial as a solid.

B. 1-(1-Trityl-1H-imidazol-4-yl)ethanol (cas #62256-50-2)

To 1-trityl-4-carboxaldehyde-1H-imidazole (11.7 g, 34.6 mmol) in THF(250 ml) at 0° C. is added methylmagnesium bromide (12.6 mL, 38 mmol,3.0 M in diethyl ether). The reaction mixture is stirred at 15° C. for 4h before quenching with water (10 mL), followed by aqueous ammoniumchloride. The reaction is extracted into ethyl acetate and washed with30 mL of saturated aqueous sodium bicarbonate. The organic solvent isremoved in vacuo. Chromatography (silica gel, ethyl acetate:hexanes, 1:1to 1:0) yields the desired product. MS (ESI) m/z 355 (M+H). (preparedsimilarly in J. Med. Chem. 1977, 20(5), 721)

C. 1-(1-Trityl-1H-imidazol-4-yl)ethanone (cas #116796-56-2)

To 1-(1-trityl-1H-imidazol-4-yl)ethanol (8.06 g, 22.7 mmol) in dioxane(400 mL) is added manganese dioxide (9.9 g, 113.8 mmol). The reactionmixture is heated to 90° C. and stirred for 18 h. The reaction isallowed to cool to room temperature and filtered through diatomaceousearth. The filtered solvent is removed in vacuo to yield the product. MS(ESI) m/z 353 (M+H) (prepared similarly in Bioorg. Med. Chem. 2004,12(9), 2251.)

D. (1-Trityl-1H-imidazol-4-yl)acetic acid (cas #168632-03-9)

Trityl chloride (51 g, 0.18 mol) is added to a suspension of(1H-imidazol-4-yl)acetic acid hydrochloride (25 g, 0.15 mol) in pyridine(500 mL). This is stirred at room temperature for 16 h, at the end ofwhich MeOH (150 mL) is added. This solution is stirred at roomtemperature for 1 h. Solvents are evaporated and the residue is taken upin CH₂Cl₂ and washed with 1 M aqueous citric acid solution (2×) andbrine. The organic phase is dried over anhydrous Na₂SO₄ and evaporatedto give a sticky residue which when taken up in diethyl ether andevaporated gave the product as a white solid that is used withoutfurther purification. MS (ESI) m/z 368.9 (M+H) (Procedure adapted fromJ. Org. Chem. 1993, 58, 4606, also prepared in WO2003013526)

E. 2-(1-Trityl-1H-imidazol-4-yl)ethanol (cas #127607-62-9)

(1-Trityl-1H-imidazol-4-yl)acetic acid (65 g, 0.17 mol) is suspended inTHF (400 mL) and cooled to 0° C. To this is added BH₃.THF solution (350mL, 1.0 M). The clear solution obtained is stirred at 0° C. for 30 minbefore warming to room temperature until LCMS indicated completion ofthe reaction. The solution is cooled again to 0° C. and quenchedcarefully with water (250 mL). The resulting solution is diluted withEtOAc (300 mL) and transferred to a separatory funnel and the aqueouslayer is extracted with EtOAc. The organic phase is dried over anhydrousNa₂SO₄ and evaporated to give a sticky residue which is taken up inethanolamine (800 mL) and heated to 90° C. for 2 h. The reaction istransferred to a separatory funnel, diluted with EtOAc (1 L) and washedwith water (3×600 mL). The organic phase is dried over anhydrous Na₂SO₄and evaporated to give 2-(1-trityl-1H-imidazol-4-yl)-ethanol as a whitesolid that is used as is without further purification. MS (ESI) m/z354.8 (M+H) (prepared by alternate method in J. Med. Chem. 1996, 39(19),3806)

F. 4-[2-(tert-Butyldimethylsilanyloxy)ethyl]-1-trityl-1H-imidazole

2-(1-Trityl-1H-imidazol-4-yl)ethanol (20 g, 56.5 mmol) is dissolved inCH₂Cl₂ (500 mL). To this is added imidazole (11.5 g, 169 mmol) andtert-butyldimethylsilylchloride (10.2 g, 67.8 mmol). The solution isstirred at room temperature until LCMS indicated the reaction iscomplete. The solution is partitioned between CH₂Cl₂ and aqueoussaturated NaHCO₃. The organic layer is washed further with aqueoussaturated NaHCO₃ and brine. The organic phase is dried over anhydrousNa₂SO₄ and evaporated to give an oil that is purified via flash columnchromatography (EtOAc/hexanes 3:7) to give3-[2-(tert-butyldimethylsilanyloxy)ethyl]-1-trityl-1H-imidazole as awhite solid. MS (ESI) m/z 469.3 (M+H).

G. Methyl 4-[(1-Trityl-1H-imidazol-4-yl)]propanoic acid ester(cas#102676-60-8)

To a white suspension of 3-(1H-imidazole-4-yl)propionic acid (5 g, 35.7mmol) in MeOH (140 mL) is added dropwise HCl/Dioxane (4M, 29 mL, 116mmol). The resulting clear solution is slowly warmed up to ambienttemperature and stirred overnight. The reaction mixture is concentratedin vacuo and dried on a high vacuum pump to give an oil.

To a solution of 3-(1H-imidazol-4-yl)propionic acid methyl esterhydrochloride (6.8 g, 35.7 mmol) in CH₃CN (160 mL) is added tritylchloride (11.0 g, 39.5 mmol) in portion at 0° C. and followed bytriethylamine (40 mL). The white suspension mixture is stirred atambient temperature overnight. The solvent is evaporated and the residueis suspended in 200 mL H₂O-ice and stirred for 1 h. The solid iscollected and dried under a high vacuum pump to give a white solid.(prepared in J. Med. Chem. 1996, 39(6), 1220.)

H. (1-Trityl-1H-Imidazol-4-yl)acetic acid methyl ester (cas#145133-11-5)

Prepared from the corresponding acid according to the procedure G above.(prepared in U.S. Pat. No. 5,140,034)

I. 4-[3-(tert-Butyldimethylsilanyloxy)propyl]-1-trityl-1H-imidazole

To a suspension of LAH (1.0 g, 26.4 mmol) in THF (80 mL) at 0° C. isadded 3-(1-trityl-1H-imidazol-4-yl)propanoic acid methyl ester (6.76 g,17.1 mmol) in portion. Then the resulting mixture is stirred at ambienttemperature overnight. The reaction is quenched with water, 15% sodiumhydroxide, and water, then diluted with methylene chloride and filtered.The precipitate on the fitter is washed with methylene chloride. Thefiltrate is evaporated to dryness to give the crude compound.

To a solution of the above crude compound (7.46 g, 20.3 mmol) in DMF (60mL) at ambient temperature is added imidazole (2.07 g, 30.4 mmol),tert-butyldimethylsilyl chloride (3.5 g, 23.2 mmol) and followed by DMAP(70 mg). The mixture is stirred at ambient temperature overnight. Themixture is partitioned between EtOAc and brine. The organic layer iswashed with brine, dried over Na₂SO₄ and concentrated to give thedesired compound.

J. 3-(1-Trityl-1H-imidazol-4-yl)butyric acid ethyl ester(cas#698367-52-1)

The title ester is prepared according to the strategy outlined inBioorg. Med. Chem. 2004, 12(9), 2273. To a suspension of NaH (60%dispersion in mineral oil, 1.7 g, 42.5 mmol) in THF (10 mL) at ambienttemperature is added dropwise triethylphosphonoacetate (8.53 mL, 42.6mmol). To this mixture is slowly added a solution of1-(1-trityl-1H-imidzaol-4-yl)ethanone (10 g, 28.4 mmol) in THF (100 mL).The resulting mixture is heated at reflux for 3 h. The reaction mixtureis poured onto ice and extracted with EtOAc. The organic layer is washedby brine, dried over anhydrous Na₂SO₄ and concentrated to give the crudesolid.

To a degassed solution of 3-(1-trityl-1H-imidazol-4-yl)but-2-enoic acidethyl ester (5 g, 11.8 mmol) in ethanol (100 mL) in a Parr bottle isadded 5% palladium on carbon (0.5 g). The bottle is purged withnitrogen, evacuated, and hydrogen gas (15 psi) added. The bottle isplaced upon a Parr hydrogenation apparatus and shaken for 18 h. Thehydrogen is evacuated and the bottle purged with nitrogen gas. Thereaction mixture is then filtered through diatomaceous earth and theclear liquid solution collected and the solvent removed in vacuo to givethe crude oil, which is subject to flash chromatography (silica gel)eluting with MeOH:CH₂Cl₂ to yield the desired compound.

K. 2,2-Dimethyl-2-(1-trityl-1H-imidazol-4-yl)-propionic acid methylester

To a solution of (1-trityl-1H-imidazol-4-yl)acetic acid methyl ester (10g, 26.2 mmol) in THF (150 mL) at 0° C. is added NaH powder (60%dispersion in mineral oil, 3.15 g, 78.8 mmol). The suspension is stirredat 0° C. for 0.5 h then is added CH₃I (4 mL, 64.1 mmol). The resultingmixture is warmed up to ambient temperature and stirred overnight. Tothe suspension mixture is added Florisil (2.5 g), and the solid isremoved by filtration through a Celite pad. The filtrate is concentratedand the residue is partitioned between EtOAc and brine, and the organiclayer is washed by brine, dried over anhydrous Na₂SO₄ and concentratedto give the crude oil, which is subject to flash chromatography (silicagel) eluting with MeOH:CH₂Cl₂ to yield the desired compound.

L. 2,2-Dimethyl-2-(1-trityl-1H-imidazol-4-yl)propionaldehyde(cas#64464-49-9)

To a solution of 2,2-dimethyl-2-(1-trityl-1H-imidazol-4-yl)propionicacid methyl ester. (4.2 g, 10.2 mmol) in THF (40 mL) at 0° C. is addedLAH (600 mg, 15.8 mmol). The resulting suspension is stirred at 0° C.for 2 h. The reaction is quenched with water, 15% sodium hydroxide; andwater, then diluted with methylene chloride and filtered. Theprecipitate on the filter is washed with methylene chloride. Thefiltrate is evaporated to dryness to give the crude compound.

To a solution of the above crude compound (3.83 g, 10.0 mmol) in CH₂Cl₂(50 mL) at ambient temperature is added Dess-Martin periodinane inportion. The resulting clear solution is stirred at ambient temperaturefor 2 h. The reaction is quenched with 1 N aqueous Na₂S₂O₃, saturatedaqueous NaHCO₃, and extracted with CH₂Cl₂. The organic layer is washedby brine, dried over anhydrous Na₂SO₄ and concentrated to give the crudeoil, which is subject to flash chromatography (silica gel) eluting withMeOH:CH₂Cl₂ to yield the desired compound. (prepared by an alternatemethod in Bioorg. Med. Chem. 2004, 12(9), 2251.)

M. 3,3-Dimethyl-3-(1-trityl-1H-imidazol-4-yl)butan-1-ol

To a suspension of methoxymethyl triphenylphosphonium chloride (11.0 g,32.1 mmol) in THF (15 mL) at ambient temperature is added t-BuOK/THE(1.0 M, 30 mL, 30 mmol). The resulting mixture is stirred at ambienttemperature about 10 min then is added a solution of2,2-dimethyl-2-(1-trityl-1H-imidazol-4-yl)propionaldehyde (3.6 g, 9.5mmol) in THF (70 mL). The mixture is stirred at ambient temperatureovernight. The reaction is quenched by sat. NH₄Cl, and the mixture ispartitioned between EtOAc and brine. The organic layer is washed bybrine, dried and concentrated to give an oil, which is subjected toflash chromatography (silica gel) eluting with MeOH:CH₂Cl₂ to yield thedesired compound.

To the above compound (1.04 g, 2.55 mmol) in 10% H₂O-THF (22 mL) atambient temperature is added TsOH resin. The mixture is stirred atambient temperature for 2 h. The reaction mixture is filtered off theresin and washed with CH₂Cl₂. The organic layer is neutralized andWashed with brine, dried and concentrated to give the crude compound.

To the above crude compound in THF (10 mL) at 0° C. is added LAH (150mg, 3.95 mmol) and the mixture is stirred at 0° C. for 3.0 min. Thereaction is quenched with water, 15% sodium hydroxide, and water, thendiluted with methylene chloride and filtered. The precipitate on thefilter is washed with methylene chloride. The filtrate is evaporated todryness to give an oil, which is subject to flash chromatography (silicagel) eluting with MeOH:CH₂Cl₂ to yield the desired compound.

N.4-[3-(tert-Butyldimethylsilanyloxy)-1,1-dimethyl-propyl]-1-trityl-1H-imidazole

To a solution of 3,3-dimethyl-3-(1-trityl-1H-imidazol-4-yl)butan-1-ol(0.87 g, 2.2 mmol) in CH₂Cl₂ (10 mL) at ambient temperature is addedimidazole (200 mg, 2.94 mmol), tert-butyldimethylsilyl chloride (350 mg,2.32 mmol). The mixture is stirred at ambient temperature overnight. Themixture is partitioned between EtOAc and brine. The organic layer iswashed with brine, dried over Na₂SO₄ and concentrated to give an oil,which is subject to flash chromatography (silica gel) eluting withMeOH:CH₂Cl₂ to yield the desired compound.

O. (E andZ)-4-[4-tert-Butyl-dimethyl-silanyloxy)-but-1-enyl]-1-trityl-1H-imidazole

To 3-(tert-butyldimethylsilanyloxy)propyl-1-bromide is converted to thetriphenyl phosphonium salt according to literature precedent(Tetrahedron Letters 1997, 38(20), 3647-3650). To the bromide (25 g, 95mmol) in toluene (200 mL) is added triphenylphosphine (40 g, 158 mmol).The reaction mixture is stirred at 105° C. for 18 h. The mixture is thenallowed to cool to room temperature over the course of an hour. Thewhite solid is filtered off, washed with hexane (50 mL), then washedwith ethyl acetate, and dried under vacuum for 24 h.

To [3-(tert-butyldimethylsilanyloxy)propyl]triphenylphosphonium bromide(35.5 g, 68.9 mmol) is added anhydrous THF (300 mL) via cannula. Thissuspension is cooled to −78° C. and n-butyllithium in hexanes (2.5 M, 30mL, 75 mmol) is added via syringe. The mixture is allowed to stir for 20minutes at −78° C. before a solution of1-trityl-4-carboxaldehyde-1H-imidazole (20.0 g, 59.1 mmol) in THF (30.0mL) is added via cannula. The mixture is allowed to warm to roomtemperature over 30 minutes, then stirred an additional 3.5 h at roomtemperature. The reaction is quenched by the addition of methanol (20mL) followed by aqueous saturated ammonium chloride. The reactionmixture is then partitioned between ethyl acetate and saturated aqueoussodium bicarbonate. The organic layer in concentrated in vacuo to yieldcrude product. Chromatography purification (silica gel, ethylacetate:hexanes 0:1 to 3:2) yields the product as a white solid, amixture of cis and trans isomers. MS (ESI) m/z 495 (M+H)

P. (E andZ)-4-[4-tert-Butyldimethylsilanyloxy)-1-methyl-but-1-enyl]-1-trityl-1H-imidazole

The title compound is prepared from Example 2C in a similar manner topreparation O above. MS (ESI) m/z 509 (M+H)

Q. 4-[4-(tert-Butyldimethylsilanyloxy)butyl]-1-trityl-1H-imidazole

To a mixture of E- andZ-4-[4-tert-butyldimethylsilanyloxy)but-1-enyl]-1-trityl-1H-imidazole(7.4 g, 14.9 mmol) in degassed ethanol in a Parr bottle is added 5%palladium on carbon (0.1 g). The bottle is purged with nitrogen,evacuated, and hydrogen gas (30 psi) added. The bottle is placed upon aParr hydrogenation apparatus and shaken for 18 hours. The hydrogen isevacuated and the bottle purged with nitrogen gas. The reaction mixtureis then filtered through diatomaceous earth and the clear liquidsolution collected and the solvent removed in vacuo to give the productas a white solid. MS (ESI) m/z 497 (M+H).

R.4-[4-(tert-Butyldimethylsilanyloxy)-1-methylbutyl]-1-trityl-1H-imidazole

The title compound is prepared from a mixture of E- andZ-4-[4-tert-butyldimethylsilanyloxy)-1-methylbut-1-enyl]-1-trityl-1H-imidazolein a similar manner to preparation Q above. MS (ESI) m/z 511 (M+H)

Example 3 A.4-[5-[2-tert-Butyldimethylsilanyloxy)ethyl]imidazol-1-ylmethyl]-3-chlorobenzonitrile

4-[2-(tert-Butyldimethylsilanyloxy)ethyl]-1-trityl-1H-imidazole (3.98 g,8.5 mmol) and 4-bromomethyl-3-chlorobenzonitrile (2.93 g, 12.7 mmol) aredissolved in MeCN (40 mL) and heated at 80° C. for 5 h. After cooling toroom temperature MeOH (40 mL) and Et₂NH (7 mL) are then added and thesolution is warmed 70° C. for 1 h. The solution is evaporated to drynessand the residue purified via flash column chromatography (acetone/CH₂Cl₂1:3→MeOH/CH₂Cl₂ 5:95) to give4-{5-[2-tert-butyl-dimethylsilanyloxy)ethyl]-imidazol-1-ylmethyl}-3-chlorobenzonitrileas an oil. MS (ESI) m/z 376.3, 378.3 (M+H).

B.{5-[2-Tert-butyldimethylsilanyloxy)ethyl]imidazol-1-yl}-(2-chloro-4-cyanophenyl)aceticacid methyl ester

4-{5-[2-tert-Butyldimethylsilanyloxy)ethyl]imidazol-1-ylmethyl}-3-chlorobenzonitrile(1.7 g, 4.52 mmol) is dissolved in anhydrous THF (30 mL) and stirred at−78° C. before a THF solution of LHMDS (8.1 mL, 1.0 M) is added. After15 min, methyl cyanoformate (0.38 mL, 4.74 mmol) is added and thesolution is left at −78° C. for 2 h. The excess LHMDS is quenched withaqueous saturated NH₄Cl and the mixture is allowed to warm to roomtemperature. The mixture is then diluted with EtOAc and washed withaqueous saturated NH₄Cl (2×). Organic is dried (Na₂SO₄) and evaporated.The crude residue is purified via flash column chromatography(EtOAc/hexanes 1:1→EtOAc) to give{5-[2-tert-butyldimethylsilanyloxy)ethyl]-imidazol-1-yl}-(2-chloro-4-cyanophenyl)aceticacid methyl ester as an oil. MS (ESI) m/z 434.3, 436.3 (M+H).

C.5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester

{5-[2-tert-Butyldimethylsilanyloxy)ethyl]imidazol-1-yl}-(2-chloro-4-cyanophenyl)-aceticacid methyl ester (2.8 g, 6.46 mmol) in THF (25 mL) is cooled to 0° C.before a solution of HCl in 1,4-dioxane (10 mL, 4.0 M, 40 mmol) isadded. After completion of the reaction as judged by LCMS, the solutionis partitioned between EtOAc and aqueous saturated NaHCO₃. The organiclayer is dried (Na₂SO₄) and evaporated to give the crude alcohol,(2-chloro-4-cyanophenyl-[5-(2-hydroxyethyl)imidazol-1-yl]-acetic acidmethyl ester that is used without further purification. MS (ESI) m/z320.1, 322.1 (M+H).

The crude(2-chloro-4-cyanophenyl)-[5-(2-hydroxyethyl)imidazol-1-yl]acetic acidmethyl ester (2.06 g, 6.46 mmol) is dissolved in CH₂Cl₂ (25 mL) andstirred at 0° C. before Et₃N (1.4 mL, 9.69 mmol) and methanesulfonylchloride (0.6 mL, 7.75 mmol) are added. After completion of thereaction, the solution is partitioned between CH₂Cl₂ and aqueoussaturated NaHCO₃. The organic layer is dried (Na₂SO₄) and evaporated togive the crude(2-chloro-4-cyanophenyl)-[5-(2-methanesulfonyloxyethyl)imidazol-1-yl]-aceticacid methyl ester that is used without further purification. MS (ESI)m/z 398.2, 400.2 (M+H).

The crude(2-chloro-4-cyanophenyl)-[5-(2-methanesulfonyloxyethyl)imidazol-1-yl]-aceticacid methyl ester (2.56 g, 6.45 mmol) is dissolved in dry DMF (50 mL)and to it is added K₂CO₃ (2.67 g, 19.4 mmol), NaI (2.9 g, 19.4 mmol) andEt₃N (2.7 mL, 19.4 mmol). The reaction is stirred at 80° C. for 2 hbefore being concentrated to dryness. The residue is then diluted withEtOAc and washed with water. The organic layer is dried (Na₂SO₄) andevaporated to give a crude residue that is purified via flash columnchromatography (Acetone/CH₂Cl₂ 1:3) to give5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester as an oil. MS (ESI) m/z 302.2, 304.2 (M+H). ¹H NMR(400 MHz, CDCl₃) δ ppm 2.64-2.76 (m, 2H), 2.97-3.06 (m, 1H), 3.84 (s,3H), 3.86-3.93 (m, 1H), 6.56 (d, J=8.1 Hz, 1H), 6.87 (s, 1H), 7.50 (obsd, J=8.1 Hz, 1H), 7.52 (s, 1H), 7.73 (s, 1H).

D.5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid

5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester (0.6 g, 2.0 mmol) is dissolved in THF/water 3:2 (20mL) and to it, is added LiOH (0.17 g, 4.0 mmol). The mixture is stirredat room temperature for 2 h before being neutralized to pH 6 with 1MHCl. The solution is evaporated to dryness to give acid,5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid as a solid. MS (ESI) m/z 288.2, 290.2 (M+H); ¹H NMR (400 MHz, MeOD)(ammonium salt) δ ppm 2.64-2.74 (m, 1H), 2.77-2.86 (m, 1H), 2.94-3.02(m, 1H), 3.74 (ddd, J=13.1, 9.1, 8.0 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H),6.85 (s, 1H), 7.59 (dd, J=8.1, 1.5 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.91(s, 1H).

E. 3-Chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile

The5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (0.02 g, 70 mol) is dissolved in DMSO (2 mL) and Et₃N (0.2 mL) andheated at 100° C. for 2 h. The solution is evaporated to dryness andresidue purified via reverse phase HPLC (5-100% MeCN/water w/0.1% TFA)to give3-chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile asa white solid. MS (ESI) m/z 244.2, 246.2 (M+H); ¹H NMR (400 MHz, CDCl₃)(TFA salt) δ ppm 2.60-2.73 (m, 1H), 3.08-3.20 (m, 2H), 3.22-3.36 (m,1H), 6.04 (dd, J=7.6, 5.8 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 7.24 (s, 1H),7.61 (d, J=8.1 Hz, H), 7.81 (d, J=1.5 Hz, 1H), 8.53 (s, 1H).

Similarly prepared are the following compounds (Table 2):

TABLE 2 Compounds of Formula (II) Structure Compound Name and AnalyticalData

5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid butyl ester. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.88 (t, J =7.33 Hz, 3 H), 1.21-1.30 (m, 2 H), 1.53-1.61 (m, 2 H), 2.60 (ddd, J =13.0, 8.4, 3.4, 1 H), 2.66-2.74 (m, 1 H), 2.92-3.00 (m, 1 H), 3.68 (ddd,J = 13.1, 9.1, 8.4 Hz, 1 H), 3.88 (s, 3 H), 4.17 (app t, J = 6.7 Hz, 2H), 6.59 (d, J = 8.1 Hz, 1 H), 6.81 (s, 1 H), 7.14 (d, J = 1.5 Hz, 1 H),7.21 (dd, J = 8.1, 1.5 Hz, 1 H), 7.52 (s, 1 H); MS (ESI) m/z 340 (M +H).

5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid ethyl ester. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.26 (t, J =7.2 Hz, 3 H), 2.62-2.74 (m, 2 H), 2.96-3.04 (m, 1 H), 3.82-3.91 (m, 1H), 4.24- 4.35 (m, 2 H), 6.55 (d, J = 8.3 Hz, 1 H), 6.86 (s, 1 H), 7.48(dd, J = 8.2, 1.6 Hz, 1 H), 7.53 (s, 1 H), 7.71 (d, J = 1.8 Hz, 1 H); MS(ESI) m/z 316, 318 (M + H).

4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-methoxybenzonitrile. ¹HNMR (400 MHz, CDCl₃) δ ppm 2.34-2.45 (m, 1 H), 2.77-2.93 (m, 2 H),3.02-3.14 (m, 1 H), 3.93 (s, 3 H), 5.68 (dd, J = 8.1, 4.0 Hz, 1 H), 6.65(d, J = 7.8 Hz, 1 H), 6.82 (s, 1 H), 7.15 (s, 1 H), 7.19 (d, J = 7.8 Hz,1 H), 7.35 (s, 1 H); MS (ESI) m/z 240 (M + H).

4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrile. ¹HNMR (400 MHz, CDCl₃) δ ppm 2.45-2.55 (m, 1 H), 2.84-2.98 (m, 2 H),3.10-3.23 (m, 1 H), 5.67 (dd, J = 8.1, 4.3 Hz, 1 H), 6.78-6.84 (m, 1 H),6.84 (s, 1 H), 7.36 (s, 1 H), 7.38-7.45 (m, 2 H); MS (ESI) m/z 228 (M +H).

2-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-5-fluorobenzonitrile. ¹HNMR (400 MHz, CDCl₃) δ ppm 2.45-2.55 (m, 1 H), 2.94 (app t, J = 7.2 Hz,2 H), 3.19-3.30 (m, 1 H), 5.73 (dd, J = 7.8, 4.8 Hz, 1 H), 6.82-6.90 (m,2 H), 7.23-7.31 (m, 1 H), 7.37 (s, 1 H), 7.44 (dd, J = 7.7, 2.7 Hz, 1H); MS (ESI) m/z 228 (M + H).

5-(2-Cyano-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester ¹H NMR (400 MHz, CDCl₃) δ ppm 2.70-2.85 (m,2 H), 2.99-3.09 (m, 1 H), 3.80-3.88 (m, 1 H), 3.90 (s, 3 H), 6.70 (dd, J= 9.0, 4.9 Hz, 1 H), 6.86 (s, 1 H), 7.20-7.26 (m, 1 H), 7.47 (dd, J =7.6, 2.8 Hz, 1 H), 7.53 (s, 1 H); MS (ESI) m/z 286 (M + H).

4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-trifluoromethylbenzonitrile.¹H NMR (400 MHz, CDCl₃) δ ppm 2.41-2.51 (m, 1 H), 2.96 (app t, J = 7.2Hz, 2 H), 3.16-3.27 (m, 1 H), 5.76 (dd, J = 7.8, 4.8 Hz, 1 H), 6.87 (brs, 1 H), 6.94 (d, J = 8.1 Hz, 1 H), 7.30 (br s, 1 H), 7.78 (d, J = 8.3Hz, 1 H), 8.02 (s, 1 H); MS (ESI) m/z 278 (M + H).

5-(4-Cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.63-2.79(m, 2 H), 2.92-3.03 (m, 1 H), 3.61-3.73 (m, 1 H), 3.81 (s, 3 H), 6.72(app t, J = 8.0 Hz, 1 H), 6.80 (s, 1 H), 7.36-7.43 (m, 2 H), 7.53 (s, 1H); MS (ESI) m/z 286 (M + H).

5-(4-Cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid. ¹H NMR (400 MHz, MeOD) (TFA salt) δ ppm 3.19 (m, J =7.2 Hz, 2 H), 3.25-3.34 (obs m, 1 H), 3.39-3.49 (m, 1 H), 7.31 (s, 1 H),7.63-7.76 (m, 3 H), 8.95 (s, 1 H); MS (ESI) m/z 272 (M + H).

5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid. ¹H NMR (400 MHz, CD₃CN) δ ppm 2.93-3.05 (m, 2 H),3.06-3.15 (m, 1 H), 3.18-3.26 (m, 1 H), 3.78 (s, 3 H), 7.00 (s, 1 H),7.30 (dd, J = 8.0, 1.4 Hz, 1 H), 7.34 (s, 1 H), 7.41 (d, J = 8.1 Hz, 1H), 8.44 (s, 1 H); MS (ESI) m/z 284 (M + H).

5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.55-2.65(m, 1 H), 2.66-2.76 (m, 1 H), 2.92-3.02 (m, 1 H), 3.63-3.74 (m, 1 H),3.77 (s, 3 H), 3.90 (s, 3 H), 6.60 (d, J = 8.1 Hz, 1 H), 6.81 (s, 1 H),7.16 (d, J = 1.3 Hz, 1 H), 7.21 (dd, J = 8.1, 1.5 Hz, 1 H), 7.51 (s, 1H); MS (ESI) m/z 298 (M + H).

5-(4-Cyano-2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.61-2.80(m, 2 H), 2.92-3.09 (m, 1 H), 3.82 (s, 3 H), 3.84-3.98 (m, 1 H), 6.59(d, J = 8.6 Hz, 1 H), 6.88 (s, 1 H), 7.45 (s, 1 H), 7.73 (d, J = 8.3 Hz,1 H), 8.03 (s, 1 H); MS (ESI) m/z 336 (M + H).

5-(2-Bromo-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.62-2.82(m, 2 H), 3.01 (dd, J = 15.2, 8.3 Hz, 1 H), 3.84 (s, 3 H), 3.86-3.97 (m,1 H), 6.51 (d, J = 8.1 Hz, 1 H), 6.86 (s, 1 H), 7.50 (s, 1 H), 7.54 (d,J = 8.3 Hz, 1 H), 7.91 (s, 1 H); MS (ESI) m/z 346, 348 (M + H).

3-Bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile. ¹HNMR (400 MHz, CDCl₃) δ d ppm 2.39-2.51 (m, 1 H), 2.77-2.98 (m, 2 H),3.15-3.29 (m, 1 H), 5.71 (dd, J = 8.3, 3.8 Hz, 1 H), 6.62 (d, J = 8.1Hz, 1 H), 6.86 (s, 1 H), 7.38 (s, 1 H), 7.52 (dd, J = 8.1, 1.5 Hz, 1 H),7.91 (s, 1 H); MS (ESI) m/z 288, 290 (M + H).

5-(3-Bromo-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester. ¹H NMR (400 MHz, CD₃CN) (TFA salt) δ ppm2.87-2.99 (m, 1 H), 2.99-3.10 (m, 2 H), 3.39-3.50 (m, 1 H), 3.85 (s, 3H), 7.23 (s, 1 H), 7.33 (dd, J = 8.3, 2.0 Hz, 1 H), 7.63 (d, J = 1.8 Hz,1 H), 7.81 (d, J = 8.3 Hz, 1 H), 8.70 (s, 1 H); MS (ESI) m/z 346, 348(M + H).

2-Bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile. ¹HNMR (400 MHz, CD₃CN) δ ppm 2.40-2.51 (m, 1 H), 2.78-2.94 (m, 2 H),3.03-3.15 (m, 1 H), 5.44 (dd, J = 8.0, 4.9 Hz, 1 H), 6.67 (s, 1 H), 7.19(dd, J = 8.1, 1.8 Hz, 1 H), 7.26 (s, 1 H), 7.48 (d, J = 1.8 Hz, 1 H),7.74 (d, J = 8.1 Hz, 1 H); MS (ESI) m/z 288, 290 (M + H).

5-(4-Cyano-2-trifluoromethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester. ¹H NMR (400 MHz, CDCl₃) δppm 2.54-2.64 (m, 1 H), 2.69-2.81 (m, 1 H), 2.95-3.08 (m, 1 H),3.74-3.81 (m, 1 H), 3.83 (s, 3 H), 6.72 (d, J = 8.1 Hz, 1 H), 6.86 (s, 1H), 7.51 (dd, J = 8.2, 1.4 Hz, 1 H), 7.53 (s, 1 H), 7.56-7.62 (m, 1 H);MS (ESI) m/z 352 (M + H).

4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-trifluoromethoxybenzonitrile. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.40-2.50 (m, 1 H), 2.83-3.00 (m, 2 H), 3.11-3.24 (m, 1 H), 5.69 (dd, J = 8.1, 4.5 Hz, 1 H), 6.86(d, J = 8.0 Hz, 1 H), 6.85 (s, 1 H), 7.32 (s, 1 H), 7.54 (dd, J = 8.1,1.3 Hz, 1 H), 7.58-7.63 (m, 1 H); MS (ESI) m/z 294 (M + H).

5-(4-Cyano-2,5-dimethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5- carboxylic acid methyl ester. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.55-2.63(m, 1 H), 2.68-2.77 (m, 1 H), 2.98 (ddd, J = 15.5, 8.7, 3.0 Hz, 1 H),3.69 (s, 4 H), 3.77 (s, 3 H), 3.82 (s, 3 H), 5.29 (s, 1 H), 6.07 (s, 1H), 6.82 (s, 1 H), 7.06 (s, 1 H), 7.55 (s, 1 H); MS (ESI) m/z 328 (M +H).

F. Chiral Resolution of Selected Compounds of Formula II Given asExample 3

1) (R) and(S)-3-Chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile

Resolution of the enantiomers of the title compound is achieved bychiral HPLC using ChiralPak IA column with a 70% EtOAc:hexane mobilephase to give enantiomer A (t_(r)=22.4 min) and enantiomer B (t_(r)=41.9min).

2) (R) and(S)-5-(2-Chloro-4-cyanophenyl)₇6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester

Resolution of the enantiomers of the title compound is achieved bychiral HPLC using ChiralPak AS column with a 15% IPA:hexane mobile phaseto give enantiomer A (t_(r)=51.8 min) and enantiomer B (t_(r)=63.2 min).

3) (R) and(S)-4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-methoxybenzonitrile

Resolution of the enantiomers of the title compound is achieved bychiral HPLC using ChiralPak AS-H column with a 1% EtOH:MeCN mobile phaseto give enantiomer A (t_(r)=16.7 min) and enantiomer B (t_(r)=25.7 min).

4) (R) and(S)-5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester

Resolution of the enantiomers of the title compound is achieved bychiral HPLC using ChiralPak AD column with a 30% IPA:hexane mobile phaseto give enantiomer A (t_(r)=31.6 min) and enantiomer B (t_(r)=41.7 min).

5) (R) and(S)-4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluorobenzonitrile

Resolution of the enantiomers of the title compound is achieved bychiral HPLC using ChiralPak AS-H column with a MeCN mobile phase to giveenantiomer A (t_(r)=16.7 min) and enantiomer B (t_(r)=22.5 min).

6) (R) and(S)-5-(4-Cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester

Resolution of the enantiomers of the title compound is achieved bychiral HPLC using ChiralPak AS column with a 20% IPA:hexane mobile phaseto give enantiomer A (t_(r)=61.4 min) and enantiomer B (t_(r)=73.8 min).

7) (R) and(S)-3-Bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile

Resolution of the enantiomers of the title compound is achieved bychiral HPLC using ChiralPak AS-H column with a 25% IPA:hexane mobilephase to give enantiomer A (t_(r)=44.0 min) and enantiomer B (t_(r)=66.0min).

8) (R) and(S)-4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-trifluoromethoxybenzonitrile

Resolution of the enantiomers of the title compound is achieved bychiral HPLC using ChiralPak AS-H column with a 10% IPA:heptane mobilephase to give enantiomer A (t_(r)=53.4 min) and enantiomer B (t_(r)=59.4min).

Example 4 A.4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-methylbenzonitrile

To a solution of3-bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile(0.100 g, 0.347 mmol) given in Example 3 (table 2) and trimethylboroxine(0.145 g, 1.04 mmol) in DME (3 mL); aqueous solutions of Na₂CO₃ (0.69mL, 2 M) and KOH (0.17 mL, 2 M) are added. After degassing withnitrogen, Pd(PPh₃)₄ (0.040 g, 0.035 mmol) is added. The mixture isheated in a microwave reactor at 130° C. 1.5 h. At that point LCMSshowed consumption of the starting material. The solution is dilutedwith ethyl acetate and saturated sodium bicarbonate. The resultingaqueous layer is extracted further with ethyl acetate (3×). The combinedorganic layers are washed with brine and dried over anhydrous sodiumsulfate. After concentration the crude product is filtered through 0.45μm filter and then purified by preparative HPLC (0% for 5 minutes and0-34% acetonitrile with 0.1% TFA in 17 minutes). MS (ESI) m/z 224.0(M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 2.33-2.42 (m, 1H), 2.43 (s, 3H),2.84-2.95 (m, 2H), 3.07-3.18 (m, 1H), 5.54 (dd, J=8.1, 4.8 Hz, 1H), 6.65(d, J=8.1 Hz, 1H), 6.83 (s, 1H), 7.32 (s, 1H), 7.41 (d, J=8:1 Hz, 1H),7.50 (s, 1H). Resolution of the (R) and (S) enantiomers of the titlecompound is achieved by chiral HPLC using ChiralPak AS-H column and 9:1hexane/EtOH to give enantiomer A (t_(r)=84 min) and enantiomer B(t_(r)=104 min).

Similarity prepared are the following:

1) 4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-vinylbenzonitrile.MS (ESI) m/z 236.2 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 2.36-2.51 (m,1H), 2.83-2.96 (m, 2H), 3.05-3.18 (m, 1H), 5.57 (d, J=11.6 Hz, 1H), 5.63(dd, J=8.1, 4.5 Hz, 1H), 5.77 (d, J=17.2 Hz, 1H), 6.69 (d, J=8.1 Hz,1H), 6.85 (s, 1H), 6.90 (dd, J=17.2, 11.1 Hz, 1H), 7.34 (s, 1H), 7.48(dd, J=8.1, 1.5 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H). Resolution of the (R)and (S) enantiomers of the title compound is achieved by chiral HPLCusing ChiralPak AS-H column with a 4:1 Heptane/IPA mobile phase to giveenantiomer A (t_(r)=32.3 min) and enantiomer B (t_(r)=58.2 min).

2)4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-((E)-propenyl)benzonitrile.MS (ESI) m/z 250.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.97 (d, J=6.6Hz, 3H), 2.37-2.49 (m, 1H), 2.82-2.95 (m, 2H), 3.04-3.18 (m, 1H), 5.62(dd, J=8.0, 4.7 Hz, 1H), 6.16-6.30 (m, 1H), 6.53 (d, J=15.4 Hz, 1H),6.66 (d, J=8.1 Hz, 1H), 6.84 (s, 1H), 7.32 (s, 1H), 7.42 (d, J=9.3 Hz,1H), 7.71 (s, 1H).

From 2-Bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrilegiven in Example 3 (table 2) the following are prepared by analogy toexample 4A:

1) 4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-vinylbenzonitrile.MS (ESI) m/z 236.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 2.43-2.56 (m,1H), 2.85-3.01 (m, 2H), 3.05-3.17 (m, 1H), 5.35 (dd, J=7.8, 5.6 Hz, 1H),5.57 (d, J=11.1 Hz, 1H), 5.90 (d, J=17.4 Hz, 1H), 6.84 (s, 1H),7.01-7.10 (m, 2H), 7.31 (s, 1H), 7.35 (d, J=1.3 Hz, 1H), 7.63 (d, J=8.1Hz, 1H).

2) 4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-methylbenzonitrileMS (ESI) m/z 224.1 (M+H); ¹H NMR (400 MHz, CD₃CN) (TFA salt) δ ppm 2.51(s, 3H), 2.52-2.61 (m, 1H), 2.94-3.20 (m, 3H), 5.65 (app t, J=6.9 Hz,1H), 7.19 (s, 1H), 7.18-7.23 (obs m, 1H), 7.26 (s, 1H), 7.70 (d, J=7.8Hz, 1H), 8.23 (s, 1H).

B.6-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-4′-fluoro-biphenyl-3-carbonitrile

To a solution of3-bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile(0.100 g, 0.347 mmol) and 4-fluorophenylboronic acid (0.158 g, 1.04mmol) in DME (2 mL), aqueous solutions of Na₂CO₃ (0.69 mL, 2 M) and KOH(0.17 mL, 2 M) are added. After degassing with nitrogen, Pd(PPh₃)₄(0.040 g, 0.035 mmol) is added. Mixture is heated in a microwave reactorat 130° C., for 20 minutes. LCMS showed consumption of startingmaterial. The solution is then diluted with ethyl acetate and saturatedaqueous sodium bicarbonate. The resulting aqueous layer is extractedfurther with ethyl acetate (3×). The combined organic layers are washedwith brine and dried over anhydrous sodium sulfate. After concentration,crude product is purified by flash chromatography (Hexane/EtOAc, andthen 10% MeOH/DCM) followed by preparative HPLC (0-50% acetonitrile with0.1% TEA in 21 minutes). After concentration and free basing,6-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-4′-fluorobiphenyl-3-carbonitrileis obtained as a white powder. MS (ESI) m/z 304.0 (M+H); ¹H NMR (400MHz, CDCl₃) δ ppm 2.38-2.54 (m, 1H), 2.76-3.03 (m, 3H), 5.33 (app t,J=6.7 Hz, 1H), 6.79 (s, 1H), 7.01 (d, J=8.1 Hz, 1H), 7.15-7.24 (m, 3H),7.29 (dd, J=13.4, 5.1 Hz, 2H), 7.54-7.65 (m, 2H).

Similarly prepared are the following:

1)6-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-4′-methoxybiphenyl-3-carbonitrileMS (ESI) m/z 316.1 (M+H); NMR (400 MHz, CDCl₃) δ ppm 2.60-2.73 (m, 1H),2.96-3.10 (m, 2H), 3.12-3.24 (m, 1H), 3.88 (s, 3H), 5.63 (app t, J=7.5Hz, 1H), 7.03 (d, J=8.6 Hz, 2H), 7.06 (d, J=8.6 Hz, 1H), 7.14 (s, 1H),7.21 (d, J=8.6 Hz, 2H), 7.65-7.70 (m, 1H), 7.66 (s, 1H), 8.32 (br s,1H).

2)2-[5-Cyano-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)phenyl]-5-fluoroindole-1-carboxylicacid tert-butyl ester. MS (ESI) m/z 443.2 (M+H)

3)4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-(5-fluoro-1H-indol-2-yl)benzonitrile.MS (ESI) m/z 343.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 2.50-2.61 (m,1H), 2.86-3.04 (m, 2H), 3.06-3.17 (m, 1H), 5.77 (dd, J=8.0, 5.4 Hz, 1H),6.56 (d, J=1.5 Hz, 1H), 6.81 (s, 1H), 6.94 (d, J=8.3 Hz, 1H), 7.01 (appdt, J=9.1, 2.5 Hz, 1H), 7.09 (s, 1H), 7.30 (dd, J=9.3, 2.3 Hz, 1H), 7.38(dd, J=8.8, 4.3 Hz, 1H), 7.57 (dd, J=8.2, 1.6 Hz, 1H), 7.85 (d, J=1.5Hz, 1H), 9.93 (br s, 1H).

From 2-Bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrilegiven in Example 3 (table 2) the following is prepared by analogy toexample 4B

5-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-4′-fluorobiphenyl-2-carbonitrile.MS (ESI) m/z 304.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 2.48-2.62 (m,1H), 2.89-3.05 (m, 2H), 3.08-3.20 (m, 1H), 5.42 (dd, J=7.7, 5.9 Hz, 1H),6.95 (s, 1H), 7.04 (app t, J=9.0 Hz, 2H), 7.13-7.21 (m, 3H), 7.46 (dd,J=8.7, 5.2 Hz, 2H), 7.54 (s, 1H).

C.4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-(n-propyl)benzonitrile

A suspension of4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-((E)-propenyl)benzonitrile(0.150 g, 0.602 mmol), 20% (w/w) palladium on carbon (0.040 g), THE (15mL), and EtOH (15 mL) is stirred under an atmosphere of hydrogen (1 atm)for 60 h. The suspension is the filtered and the filtrate concentrated.The residue is then purified by flash chromatography (Hexane/EtOAc, andthen 10% MeOH/EtOAc) to give4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-(n-propyl)benzonitrileas a white solid. MS (ESI) m/z 252.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δppm 1.04 (t, J=7.3 Hz, 3H), 1.63-1.77 (m, 2H), 2.33-2.45 (m, 1H),2.62-2.80 (m, 2H), 2.92 (app t, J=7.1 Hz, 2H), 3.04-3.19 (m, 1H), 5.58(dd, J=7.8, 5.6 Hz, 1H), 6.73 (d, J=8.1 Hz, 1H), 6.81 (s, 1H), 7.25 (s,1H), 7.41 (d, J=8.1 Hz, 1H), 7.51 (s, 1H).

Similarly prepared are the following:

1) 4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-ethylbenzonitrile.MS (ESI) m/z 238.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.34 (t, J=7.6Hz, 3H), 2.34-2.47 (m, 1H), 2.68-2.88 (m, 2H), 2.89-2.97 (m, 2H),3.07-3.19 (m, 1H), 5.59 (dd, J=7.8, 5.1 Hz, 1H), 6.72 (d, J=8.1 Hz, 1H),6.84 (s, 1H), 7.28 (s, 1H), 7.43 (dd, J=8.1, 1.8 Hz, 1H), 7.55 (d, J=1.3Hz, 1H). Resolution of the (R) and (S) enantiomers of the title compoundis achieved by chiral HPLC using ChiralPak AS-H column and 4:1heptane/i-PrOH to give enantiomer A (t_(r)=28.1 min) and enantiomer B(t_(r)=43.1 min).

2) 4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-ethylbenzonitrile.MS (ESI) m/z 238.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.28 (t, J=7.5Hz, 3H), 2.37-2.55 (m, 1H), 2.78-3.01 (m, 4H), 3.02-3.18 (m, 1H),5.26-5.40 (m, 1H), 6.82 (br s, 1H), 6.99 (d, J=7.1 Hz, 1H), 7.05 (br s,1H), 7.30 (br s, 1H), 7.60 (d, J=7.8 Hz, 1H).

D. 4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-ethoxybenzonitrile

A solution of3-bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile(0.090 g, 0.312 mmol) given in Example 3 (table 2), Pd₂(dba)₃ (0.029 g,0.031 mmol), BINAP (0.039 g, 0.062 mmol), Cs₂CO₃ (0.204 g, 0.625 mmol),EtOH (0.091 mL, 1.54 mmol), and DME (4 mL) is heated in a microwavereactor at 135° C. for 1.5 h. At that point LCMS showed consumption ofthe starting material. The mixture is filtered and then the filtrate isconcentrated. The residue is then purified by flash chromatography(0-10% MeOH/DCM) give4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-ethoxybenzonitrile. MS(ESI) m/z 254.1 (M+H); ¹H NMR (400 MHz, MeOD) (TFA salt) δ ppm 1.32 (t,J=6.9 Hz, 3H), 2.69-2.82 (m, 1H), 3.07-3.22 (m, 3H), 4.02-4.22 (m, 2H),5.92-6.03 (m, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.31 (s, 1H), 7.36 (dd,J=7.8, 1.5 Hz, 1H), 7.43 (d, J=1.3 Hz, 1H), 8.68 (s, 1H).

Similarity prepared are the following:

3-Butoxy-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile. MS(ESI) m/z 282.1 (M+H); NMR (400 MHz, CDCl₃) δ ppm 1.01 (t, J=7.3 Hz,3H), 1.46-1.59 (m, 2H), 1.78-1.88 (m, 2H), 2.38-2.49 (m, 1H), 2.77-2.93(m, 2H), 3.02-3.15 (m, 1H), 4.06 (app t, J=6.3 Hz, 2H), 5.67 (dd, J=8.2,4.2 Hz, 1H), 6.66 (d, J=7.8 Hz, 1H), 6.82 (s, 1H), 7.13 (d, J=1.3 Hz,1H), 7.17 (dd, J=7.8, 1.3 Hz, 1H), 7.36 (s, 1H).

From 2-Bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrilegiven in Example 3 (table 2) the following is prepared by analogy toexample 4D:

1) 4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-methoxybenzonitrile.MS (ESI) m/z 240.1 (M+H); ¹H NMR (400 MHz, CD₃CN) (TFA salt) δ ppm2.97-3.17 (m, 4H), 3.91 (s, 3H), 5.65 (app t, J=7.2 Hz, 1H), 6.90 (dd,J=8.0, 1.4 Hz, 1H), 7.01 (d, J=1.3 Hz, 1H), 7.19 (s, 1H), 7.65 (d, J=8.1Hz, 1H), 8.23 (s, 1H).

2)4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-pyrrolidin-1-yl-benzonitrile.MS (ESI) m/z 279.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.97-2.03 (m,4H), 2.44-2.58 (m, 1H), 2.85-2.98 (m, 2H), 2.99-3.13 (m, 1H), 3.53-3.60(m, 4H), 5.25 (dd, J=7.7, 5.9 Hz, 1H), 6.26 (d, J=1.3 Hz, 1H), 6.38 (dd,J=8.1, 1.5 Hz, 1H), 6.85 (s, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.44 (s, 1H).

E.3-Fluoro-4-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile

A solution of4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-4-fluorobenzonitrile(0.050 g, 0.220 mmol) given in Example 3 (table 2), 18-crown-6 (0.006 g,0.022 mmol), and THF (2 mL) is cooled to −78° C. KHMDS (0.66 mL, 0.5 M)is then added. After 20 min MeI (0.07 mL, 1.10 mmol) is added. After 2.5h the solution is diluted with saturated aqueous NaHCO₃ and DCM. Theaqueous layer is further extracted with DCM (3×20 mL). The combinedorganic layers are dried (Na₂SO₄), filtered and concentrated. Theresidue is purified via flash chromatography (50-100% EtOAc/hexanes) togive3-fluoro-4-(5-methyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrileas a white solid. MS (ESI) m/z 242.0 (M+H); ¹H NMR (400 MHz, CDCl₃) δppm 2.01 (s, 3H), 2.49-2.62 (m, 1H), 2.73-2.99 (m, 3H), 6.35 (app t,J=8.0 Hz, 1H), 6.84 (s, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.40 (d, J=10.9 Hz,1H), 7.55 (s, 1H).

F.3-Fluoro-4-(7-methylene-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile

3-Fluoro-4-(5-iodo-imidazol-1-ylmethyl)benzonitrile

A mixture of 4-iodo-1-trityl-1H-imidazole (17.1 g, 39.2 mmol) and4-bromomethyl-3-fluorobenzonitrile (9.65 g, 45.08 mmol) in 150 mL of dryacetonitrile is stirred at room temperature for 7 days. Afterconcentration, the residue is mixed with methanol, and heated to refluxfor 1.5 h. The solvent is subsequently removed and the residue istreated with 1M HCl (300 mL). The resulting suspension is filtered andthe washed with HCl (1 M). The combined solution is adjusted to PH 9-10by saturated NaHCO₃ solution. The resulting precipitation is collectedby filtration, dried in vacuum oven. MS (ESI) m/z (M+H) 328.1.

3-Fluoro-4-[1-(5-iodo-imidazol-1-yl)-but-3-enyl]benzonitrile

LDA (1.5 M in THF, 20.85 mL, 31.7 mmol) is added dropwise to asuspension of 3-Fluoro-4-(5-iodo-imidazol-1-ylmethyl)benzonitrile (7.98g, 24.4 mmol) in 150 mL of dry THF at −78° C. After 1 h at thistemperature, allyl bromide (2.09 mL, 24.4 mmol) is added slowly, and theresulting mixture is stirred at −78° C. for 3 h. The reaction isquenched with saturated NH₄Cl solution, and extracted with CH₂Cl₂. Thecombined extracts are washed with brine and dried over anhydrous Na₂SO₄.After filtration and concentration, the residue is purified by flashcolumn. MS (ESI) m/z (M+H) 368.0.

A mixture of3-Fluoro-4-[1-(5-iodo-imidazol-1-yl)-but-3-enyl]benzonitrile (2.14 g,5.83 mmol), PS-PPh₃-Pd (0.06 mmol) and Et₃N (4.0 mL, 29.15 mmol) in 20mL of DMF is heated at 150° C. by microwave for 1 h. After filtrationand evaporation, the residue is mostly dissolved by 1 M HCl solution.The resulting black mixture is filtered, and the solution issubsequently adjusted to PH 9-10 by saturated NaHCO₃ solution. Theresulting mixture is extracted with CH₂Cl₂, and the combined extractsare washed with brine and dried over anhydrous Na₂SO₄. After filtrationand concentration, the residue is purified by flash column. MS (ESI) m/z240.3 (M+H); ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.33 (m, 2H), 7.32 (s, 1H),7.18 (s, 1H), 6.82 (t, J=8.0 Hz, 1H), 5.71 (dd, J=12.0 Hz, 4.0 Hz, 1H),5.35 (t, J=4.0 Hz, 1H), 4.98 (t, J=4.0 Hz, 1H), 3.83-3.76 (m, 1H),3.05-2.99 (m, 1H). Resolution of the enantiomers of the title compoundis achieved by chiral HPLC using the ChiralPak IA column with aEtOH-hexanes (20%, v/v) mobile phase to give enantiomer A (t_(r)=21 min)and enantiomer B (t_(r)=25 min).

G.5′-[2-fluoro-4-cyano-phenyl]-5′,6′-dihydrospiro[cyclopropane-1,7′-pyrrolo[1,2-c]imidazole]

A solution of TFA (0.234 mL, 3 mmol) in 0.6 mL of dry CH₂Cl₂ is addeddropwise to a solution of Et₂Zn (1M in Hexanes, 3.06 mL, 3.06 mmol) at0° C. The resulting suspension is subsequently treated with a solutionof CH₂I₂ (0.246 mL, 3.06 mmol) in CH₂Cl₂ (0.4 mL). After 2 h at 0° C., asolution of3-fluoro-4-(7-methylene-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile(333.8 mg, 1.392 mmol) in CH₂Cl₂ is added. After overnight, the reactionis quenched with saturated NaHCO₃ solution, and extracted with CH₂Cl₂(20 mL×4). The combined extracts are washed with brine, dried overanhydrous Na₂SO₄. After filtration and evaporation, the residue ispurified by chromatography and yield 112 mg of oil. MS (ESI) m/z 254.2(M+H). ¹H NMR (400.3 MHz, CDCl₃): δ 8.93 (s, 1H), 7.54-7.52 (m, 1H),7.45 (d, J=8.00 Hz, 1H), 7.35 (m, 1H), 6.83 (s, 1H), 6.27 (brs, 1H),3.22 (m, 1H), 2.61 (d, J=12 Hz, 1H), 1.33-1.19 (m, 2H), 1.16-1.14 (m,1H), 0.90-0.85 (m, 1H).

Example 5 A.5-(3-Fluoro-4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester

4-[2-(tert-Butyl-dimethylsilanyloxy)ethyl]-1-trityl-1H-imidazole (6.5 g,14.0 mmol) and bromo-(3-fluoro-4-methoxyphenyl)acetic acid methyl ester(5.8 g, 21.0 mmol) are stirred in 60 mL MeCN at room temperature for 2days. At that point MeOH (50 mL) and Et₂NH (50 mL) are then added andthe resulting solution heated at 75° C. for 0.5 h. The solution isevaporated and the residue purified via flash column chromatography(EtOAc/DCM 1:9→EtOAc/DCM 1:1) to give{5-[2-(tert-butyldimethylsilanyloxy)ethyl]-imidazol-1-yl}-(3-fluoro-4-methoxyphenyl)aceticacid methyl ester as an oil. MS (ESI) m/z 423.3 (M+H).

The{5-[2-(tert-butyldimethylsilanyloxy)ethyl]-imidazol-1-yl}-(3-fluoro-4-methoxyphenyl)-aceticacid methyl ester (3.1 g, 7.34 mmol) is dissolved in THF (1.00 mL) andcooled down to 0° C. and then HCl in dioxane (11 mL, 4.0 M) is added.After 2 h the solution is evaporated to dryness and the resultingalcohol,(3-fluoro-4-methoxyphenyl)[5-(2-hydroxy-ethyl)-imidazol-1-yl]acetic acidmethyl ester, is used without further purification. MS (ESI) m/z 309.2(M+H).

The (3-fluoro-4-methoxyphenyl)-[5-(2-hydroxyethyl)imidazol-1-yl]-aceticacid methyl ester (2.26 g, 7.34 mmol) is dissolved in DCM (100 mL) andcooled down to 0° C. before Et₃N (5.1 mL, 36.7 mmol) and methanesulfonylchloride (0.7 mL, 8.81 mmol) are added. After 1 h, the solution istransferred to a separatory funnel and partitioned between DCM andsaturated aqueous NaHCO₃. The organic is dried (Na₂SO₄) and evaporatedto give a crude residue that is purified via flash column chromatography(DCM→MeOH/DCM 5:95) to give the pure intermediate mesylate as yellowoil. MS (ESI) m/z 387.2 (M+H).

The above mesylate (1.8 g, 4.66 mmol) is dissolved in dry THF (50 mL)and cooled down to −78° C. To this solution is added LHMDS (5.6 mL, 1.0MTHF). The solution is then allowed to warm gradually to room temperatureover 12 h. The solution is then partitioned between EtOAc and saturatedaqueous NH₄Cl. The organic layer is dried (Na₂SO₄) and concentrated. Theresidue is purified via flash column chromatography (DCM→MeOH/DCM 5:95)to give5-(3-fluoro-4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester. MS (ESI) m/z 291.2 (M+H); ¹H NMR (400 MHz, CDCl₃) δppm 2.64-2.86 (m, 3H), 3.31-3.40 (m, 1H), 3.79 (s, 3H), 3.84 (s, 3H),6.62-6.68 (m, 1H), 6:76 (s, 1H), 6.80-6.89 (m, 2H), 7.72 (s, 1H).

B. 5-(3-fluoro-4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole

5-(3-fluoro-4-methoxy-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester (0.530 g, 1.82 mmol) is dissolved in THF/water (20 mL)(3:2) and to the solution is added LiOH (0.230 g, 9.58 mmol). After 1 h,the solution is brought to pH 4-5 with 1 M HCl and then evaporated todryness to give5-(3-fluoro-4-methoxy-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid that is used without further purification. MS (ESI) m/z 277.2(M+H).

The above acid (0.500 g, 1.81 mmol) is dissolved in DMSO (8.0 mL) andEt₃N (3.0 mL) and heated in a microwave reactor at 200° C. for 0.5 h.The solution is evaporated to dryness and purified via flash columnchromatography (MeOH/DCM 5:95→MeOH/DCM 1:9) to give5-(3-fluoro-4-methoxy-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole asa pale yellow solid. MS (ESI) m/z 233.3 (M+H); ¹H NMR (400 MHz, CDCl₃) δppm 2.44-2.58 (m, 1H), 2.81-3.11 (m, 3H), 3.91 (s, 3H), 5.25 (app t,J=6.8 Hz, 1H), 6.82-6.91 (m, 3H), 6.95 (app t, J=8.6 Hz, 1H), 7.35 (s,1H).

Example 5a A.4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3,5-difluorobenzonitrile

3-(1-Trityl-1H-imidazol-4-yl)propionic acid methyl ester (7.75 g, 19.5mmol), J. Org. Chem. 2000, 65, 2229-2230, is dissolved in DCM (300 mL)and cooled to −78° C. To this is added a toluene solution of DIBAL (21.0mL, 1.5 M). After 2 h MeOH (20 mL) is added followed by saturatedaqueous Rochelle salt solution (50 mL). The mixture is partitionedbetween DCM and saturated aqueous Rochelle salt solution. The organicphase is dried (Na₂SO₄) and evaporated. The crude residue is purifiedvia flash column chromatography (MeOH/DCM 1:99→MeOH/DCM 5:95) to givethe aldehyde, 3-(1-trityl-1H-imidazol-4-yl)propionaldehyde as a yellowgum (cas #184030-88-4). ¹H NMR (CDCl₃) δ 9.83 (s, 1H), 7.38-7.31 (m,10H), 7.16-7.12 (m, 6H), 6.58 (s, 1H), 2.90 (t, J=8.0 Hz, 2H), 2.83-2.79(m, 2H).

Diisopropylamine (0.53 mL, 3.75 mmol) is dissolved in 5 mL THF andcooled down to −78° C. To this is added n-BuLi (2.3 mL, 1.6M inhexanes). After 15 min, a solution of 3,5-difluorobenzonitrile (0.52 g,3.75 mmol) and THF (5 mL) is added and the solution maintained at thattemperature for 0.5 h before adding a solution of3-(1-trityl-1H-imidazol-4-yl)propionaldehyde and THF (20 mL). After 2 h,the solution is diluted with EtOAc and quenched with saturated aqueousNH₄Cl. The mixture is then partitioned between EtOAc and saturatedaqueous NH₄Cl. The organic is dried (Na₂SO₄) and evaporated. The residueis purified via flash column chromatography (EtOAc/hexanes 2:8→EtOAc) togive3,5-difluoro-4-[1-hydroxy-3-(1-trityl-1H-imidazol-4-yl)-propyl]benzonitrileas a yellow powder. MS (ESI) m/z 506.2 (M+H).

3,5-Difluoro-4-[1-hydroxy-3-(1-trityl-1H-imidazol-4-yl)-propyl]benzonitrile(0.105 g, 0.21 mmol) is dissolved in DMF (5 mL) and cooled down to 0° C.To this is added Et₃N (0.043 mL, 0.31 mmol) and methanesulfonyl chloride(0.019 mL, 0.25 mmol). After 2 h, LCMS showed the presence of theintermediate mesylate [MS (ESI) m/z 584.3 (M+H)]. The solution isevaporated to dryness and dissolved in DMF (5 mL), to which is addedK₂CO₃ (0.086 g, 0.62 mmol) and NaI (0.093 g, 0.62 mmol) and the mixtureis heated to 90° C. for 0.5 h. The solution is then evaporated,dissolved in MeCN and filtered. The crude residue is purified via flashcolumn chromatography (MeOH/DCM 1:99→MeOH/DCM 1:9) to give4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3,5-difluorobenzonitrile.MS (ESI) m/z 246.2 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 2.72-2.85 (m,1H), 2.93-3.05 (m, 1H), 3.08-3.21 (m, 2H), 5.75 (app t, J=7.2 Hz, 1H),6.79 (s, 1H), 7.18-7.41 (m, 3H).

B.4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-5-methoxybenzonitrile

Conditions used to synthesize3-fluoro-4-[1-hydroxy-3-(1-trityl-1H-imidazol-4-yl)-propyl]-5-methoxybenzonitrileare similar to the procedure above for the synthesis of3,5-difluoro-4-[1-hydroxy-3-(1-trityl-1H-imidazol-4-yl)-propyl]benzonitrile.MS (ESI) m/z 537.2 (M+H).

3-fluoro-4-[1-hydroxy-3-(1-trityl-1H-imidazol-4-yl)-propyl]-5-methoxybenzonitrile(0.283 g, 0.55 mmol) is dissolved in DCM (5 mL) to which thionylchloride (0.12 mL, 1.64 mmol) is added. The solution is heated at refluxfor 1 h before the reaction is allowed to cool to ambient temperatureand partitioned between DCM and saturated aqueous NaHCO₃. The organic isdried (Na₂SO₄) and evaporated.

The crude chloride is dissolved in DMF (5 mL), to which is added K₂CO₃(0.243 g, 1.76 mmol) and NaI (0.25 g, 1.66 mmol) and the mixture isheated to 120° C. for 0.5 h in a microwave. The solution is thenevaporated, dissolved in MeCN and filtered. The crude residue ispurified via flash column chromatography (MeOH/DCM 1:99→MeOH/DCM 1:9)and finally HPLC to give4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-5-methoxybenzonitrileas the TFA salt. MS (ESI) m/z 258.3 (M+H); ¹H NMR (400 MHz, CDCl₃) (TFAsalt) δ ppm 2.79-2.93 (m, 1H), 3.05-3.19 (m, 2H), 3.19-3.31 (m, 1H),3.86 (s, 3H), 6.05 (app t, J=7.6 Hz, 1H), 7.03 (s, 1H), 7.07 (s, 1H),7.10 (dd, J=9.6, 1.3 Hz, 1H), 8.32 (s, 1H).

Example 6 A.4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-nitrobenzonitrile

3-[2-(tert-Butyldimethylsilanyloxy)ethyl]-1-trityl-1H-imidazole (1.00 g,2.13 mmol) and 4-bromomethyl-3-nitrobenzonitrile (cas#223512-70-7,prepared in WO9919301) (0.77 g, 3.20 mmol), prepared via the generalbenzylic bromination procedure described earlier, are dissolved in MeCN(11 mL) and stirred at room temperature for 15 h. At that time thesolution is diluted with MeOH (5 mL) and Et₂NH (1 mL) and then warmed to70° C. for 1.5 h. The solution is then evaporated to dryness and theresidue purified via flash column chromatography (20-100% EtOAc/hexanes)to give4-{5-[2-(tert-butyldimethylsilanyloxy)ethylimidazol-1-ylmethyl}-3-nitrobenzonitrileas an oil. MS (ESI) m/z 387.0 (M+H).

4-{5-[2-(tert-Butyldimethylsilanyloxy)ethyl]imidazol-1-ylmethyl}-3-nitrobenzonitrile(0.540 g, 1.40 mmol) is dissolved in THF (8 mL) and MeOH (2 mL) andcooled to 0° C. Then a dioxane solution of HCl (1.75 mL, 4.0 M, 7 mmol)is added. After 0.5 h, the solution is concentrated.

The crude residue,4-[5-(2-hydroxyethyl)imidazol-1-ylmethyl]-3-nitrobenzonitrile, is thentaken up in CH₂Cl₂ (10 mL), cooled to 0° C., and treated with Et₃N (0.58mL, 4.19 mmol). To this solution is added methanesulfonyl chloride (0.13mL, 1.68 mmol). After 0.5 h the solution is diluted with CH₂Cl₂ (10 mL)and saturated aqueous NaHCO₃ (20 mL). The organic layer is furtherextracted with CH₂Cl₂ (3×20 mL) and the combined layers are dried(Na₂SO₄) and concentrated to give crude methanesulfonic acid2-[3-(4-cyano-2-nitrobenzyl)-3H-imidazol-4-yl]ethyl ester. A suspensionof the methanesulfonic acid2-[3-(4-cyano-2-nitrobenzyl)-3H-imidazol-4-yl]-ethyl ester residue, DMF(17 mL), sodium iodide (0.630 g, 4.19 mmol), Et₃N (0.58 mL, 4.19 mmol),and potassium carbonate (0.580 g, 4.19 mmol) is heated to 60° C. for 1hour and then 75° C. for an additional 2 h. At that point the suspensionis concentrated and diluted with CH₂Cl₂ (20 mL) and saturated aqueousNaHCO₃ (20 mL). The organic layer is further extracted with CH₂Cl₂ (3×20mL) and the combined layers are dried (Na₂SO₄). The residue is thenpurified via HPLC (reversed phase, CH₃CN/H₂O) to give4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-nitrobenzonitrile as asolid. MS (ESI) m/z 254.9 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 2.48-2.57(m, 1H), 2.81-2.92 (m, 1H), 2.92-3.01 (m, 1H), 3.35-3.47 (m, 1H), 6.03(dd, J=8.6, 3.5 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.89 (s, 1H), 7.36 (s,1H), 7.81 (dd, J=7.8, 1.8 Hz, 1H), 8.41 (d, J=1.8 Hz, 1H).

B. 3-Amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile

4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-nitrobenzonitrile(0.054 g, 0.212 mmol) is dissolved in THF (2 mL) and EtOH (2 mL) and 5%palladium on carbon (wet) (15 mg) is then added. The mixture is placedunder an atmosphere of hydrogen overnight. The mixture is then filteredand concentrated. The residue is purified via HPLC (reversed phase,CH₃CN/H₂O) to give3-amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile as asolid. MS (ESI) m/z 225.0 (M+H); ¹H NMR (400 MHz, CH₃CN) (TFA salt) δppm 2.45-2.57 (m, 1H), 2.99-3.16 (m, 3H), 4.47 (br s, 2H), 5.68-5.75 (m,1H), 6.69 (d, J=7.8 Hz, 1H), 6.98 (d, J=1.5 Hz, 1H), 7.09 (d, J=1.8 Hz,1H), 7.21 (s, 1H), 8.32 (s, 1H).

C.1-[5-Cyano-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)phenyl]-3-ethylurea

To a solution of3-Amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile(0.090 g, 0.420 mmol), given as example 6B, and DMF (5 mL) is addedethylisocyanate (0.040 mL, 0.510 mmol). The solution is heated to 70° C.in a microwave reactor for 1.5 h followed by heating at 70° C. in an oilbath overnight. The solution is then concentrated and the residuepurified via flash chromatography (1-10% MeOH/CH₂Cl₂) to give1-[5-Cyano-2-(6,7-dihydro-5H-pyrrolo[1,2-d]imidazol-5-yl)phenyl]-3-ethylurea.MS (ESI) m/z 296.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.16 (t, J=7.2Hz, 3H), 2.47-2.62 (m, 1H), 2.82-3.04 (m, 2H), 3.05-3.17 (m, 1H),3.21-3.33 (m, 2H), 5.63 (app t, J=6.8 Hz, 1H), 5.80 (br s, 1H), 6.82 (s,1H), 6.91 (d, J=8.1 Hz, 1H), 7.30 (dd, J=8.1, 1.5 Hz, 1H), 7.39 (s, 1H),7.53 (br s, 1H), 7.97 (d, J=1.3 Hz, 1H).

D.N-[5-Cyano-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-phenyl]-butyramide

A DMF (3 mL) solution of3-Amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile(0.095 g, 0.42 mmol), given as example 6B, is treated with Et₃N (0.09mL, 0.64 mmol) and butyryl chloride (0.05 mL, 0.51 mmol) at roomtemperature. After 1 h the solution is concentrated. Purification viaprep HPLC givesN-[5-Cyano-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-phenyl]-butyramide.MS (ESI) m/z 295.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.01 (t, J=7.3Hz, 3H), 1.67-1.80 (m, 2H), 2.35 (t, J=7.5 Hz, 2H), 2.49-2.61 (m, 1H),2.88-3.01 (m, 2H), 3.05-3.18 (m, 1H), 5.56 (dd, J=8.0, 5.9 Hz, 1H), 6.84(s, 1H), 6.97 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 7.45 (dd, J=8.1, 1.5 Hz,1H), 7.70 (br s, 1H), 7.91 (s, 1H).

Example 7 A,5-(4′-fluorobiphenyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole

To a suspension of 2-(1-trityl-1H-imidazol-4-yl)ethanol (0.65 g, 1.80mmol), acetonitrile (9 mL) and CH₂Cl₂ (12 mL) is added a solution of2-bromomethyl-4′-fluorobiphenyl (0.478 g, 1.80 mmol) in CH₂Cl₂ (2 mL).The resulting mixture is stirred at room temperature overnight. Thesolution is concentrated and the residue is taken up in MeOH and heatedto 75° C. for 3.5 h. The solution is then concentrated and the residueis partitioned between CH₂Cl₂ and aqueous 5% NaHCO₃. The aqueous layeris then extracted with CH₂Cl₂ (3×). The combined organic layers are thenwashed with brine and dried over Na₂SO₄. The residue is then purified byflash chromatography (CH₂Cl₂/MeOH) give2-[3-(4′-fluorobiphenyl-2-ylmethyl)-3H-imidazol-4-yl]ethanol. MS (ESI)m/z 297.1 (M+H).

To a solution of2-[3-(4′-fluorobiphenyl-2-ylmethyl)-3H-imidazol-4-yl]ethanol (0.341 g,1.15 mmol) in CH₂Cl₂ (10 mL) is added, thionyl chloride (0.11 mL, 1.50mmol) at 0° C. The mixture is then heated to reflux for 3 h before thesolvent is removed and the residue dried under reduced pressure to give5-(2-chloroethyl)-1-(4′-fluorobiphenyl-2-ylmethyl)-1H-imidazole. Theresidue is taken up in THF (60 mL). TMEDA (0.71 ml, 4.72 mmol) is added,followed by a hexane/THF solution of LDA (2.62 mL, 1.8 M) at −78° C. Theresulting mixture is stirred at −78° C. for 5 h. The excess LDA is thenquenched by the addition of saturated NH₄Cl. The mixture is then dilutedwith CH₂Cl₂ and water. The organic layer is separated and washed withwater, brine and dried over Na₂SO₄. After concentration, the residue ispurified by flash chromatography (CH₂Cl₂/MeOH) to give5-(4′-fluorobiphenyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole. MS(ESI), m/z 279.1 (M+H). Resolution of the (R) and (S) enantiomers of thetitle compound is achieved by chiral HPLC using ChiralPak AD column and13% IPA:hexane to give enantiomer A (t_(r)=9.6 min) and enantiomer B(t_(r)=12.6 min). For enantiomer B: ¹H NMR (400 MHz, CDCl₃) (HCl salt) δppm 2.68-2.79 (m, 1H), 2.95-3.06 (m, 2H), 3.13-3.22 (m, 1H), 5.55 (appt, J=7.6 Hz, 1H), 6.96 (dd, J=7.6, 1.5 Hz, 1H), 7.13 (s, 1H), 7.18 (appt, J=8.6 Hz, 2H), 7.27-7.32 (m, 2H), 7.33-7.38 (m, 1H), 7.40-7.49 (m,2H), 8.01 (s, 1H).

Similarly prepared is the following:

5-Biphenyl-2-yl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole. MS (ESI) m/z261.3 (M+H). Resolution of the (R) and (S) enantiomers of the titlecompound is achieved by chiral HPLC using ChiralPak AD column and 13%IPA:hexane to give enantiomer A (t_(r)=9.1 min) and enantiomer B(t_(r)=12.4 min). For enantiomer B: ¹H NMR (400 MHz, MeOD) (TFA salt) δppm 2.65-2.74 (m, 1H), 3.00 (ddd, J=15.6, 10.8, 8.5 Hz, 2H), 3.09-3.19(m, 1H), 5.67-5.73 (m, 1H), 7.08-7.14 (m, 1H), 7.27 (s, 1H), 7.32-7.41(m, 3H), 7.42-7.50 (m, 5H), 8.66 (s, 1H).

Example 8 A.5-(4-Cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid isopropyl ester

To a solution of5-(4-cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester (0.186 g, 0.652 mmol) in THF (15 mL), an aqueoussolution of LiOH (0.065 mL, 2 M) is added. The solution is stirred atroom temperature for 20 min, at which time LCMS showed only startingmaterial. At that time additional H₂O (1.5 mL) is added. After anadditional 1 h the starting material had been consumed. The solution isthen neutralized to pH 5-6 with 1 N HCl and evaporated to dryness. Thecrude acid,5-(4-cyano-2-fluoro-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid is used without further purification. MS (ESI) m/z 272.0 (M+H).

5-(4-Cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (0.15 g, 0.279 mmol) is suspended in CH₂Cl₂ (3 mL) and DMF (0.01ml) and cooled to 0° C. A solution of oxalyl chloride (0.31 mL, 2 M) inCH₂Cl₂ is added dropwise. After 1 h i-PrOH (3 mL) is added. After 2 hEt₃N is added until basic and the solution is concentrated. Theresulting slurry is dissolved in CH₂Cl₂, washed with aqueous saturatedNaHCO₃/H₂O (1:1) and brine, then dried over Na₂SO₄. After concentration,the residue is purified by HPLC (2-38% MeCN/H₂O containing 0.1% TFA) togive5-(4-cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid isopropyl ester as solid. MS (ESI) m/z 314.0 (M+H); ¹H NMR (400MHz, CD₃CN) (TFA salt) δ ppm 1.22 (d, J=6.06 Hz, 3H), 1.23 (d, J=6.06Hz, 3H), 3.01-3.18 (m, 3H), 3.38-3.45 (m, 1H), 5.08-5.18 (m, 1H), 7.20(s, 1H), 7.34 (app t, J=8.08 Hz, 1H), 7.62-7.68 (m, 2H) 8.52 (s, 1H).

Similarly prepared are the following:

1)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid isopropyl ester. MS (ESI) m/z 330.2, 332.2 (M+H); ¹H NMR (400 MHz,CDCl₃) δ ppm 1.23 (d, J=6.3 Hz, 3H), 1.27 (d, J=6.3 Hz, 3H), 2.63-2.77(m, 2H), 2.94-3.07 (m, 1H), 3.81-3.93 (m, 1H), 5.09-5.22 (m, 1H), 6.54(d, J=8.1 Hz, 1H), 6.89 (s, 1H), 7.50 (dd, J=8.2, 1.6 Hz, 1H), 7.58 (s,1H), 7.73 (d, J=1.5 Hz, 1H).

2)5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid isopropyl ester. MS (ESI) m/z 326.3 (M+H); ¹H NMR (400 MHz, CDCl₃)δ ppm 1.18 (d, J=6.3 Hz, 3H), 1.23 (d, J=6.3 Hz, 3H), 2.55-2.64 (m, 1H),2.65-2.76 (m, 1H), 2.97 (ddd, J=15.4, 9.4, 2.8 Hz, 1H), 3.61-3.71 (m,1H), 3.88 (s, 3H), 5.04-5.14 (m, 1H), 6.57 (d, J=8.1 Hz, 1H), 6.83 (s,1H), 7.14 (d, J=1.3 Hz, 1H), 7.21 (dd, J=8.0, 1.4 Hz, 1H), 7.58 (s, 1H).

3)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid 2-isopropoxyethyl ester. MS (ESI) m/z 374.2, 376.2 (M+H); ¹H NMR(400 MHz, CDCl₃) (HCl salt) δ ppm 1.08 (d, J=6.1 Hz, 3H), 1.10 (d, J=6.1Hz, 3H), 2.89-3.02 (m, 2H), 3.17-3.28 (m, 1H), 3.52-3.59 (m, 1H), 3.61(app t, J=4.5 Hz, 2H), 3.88-3.96 (m, 1H), 4.25-4.33 (m, 1H), 4.57-4.65(m, 1H), 6.73 (d, J=8.1 Hz, 1H), 7.29 (s, 1H), 7.61 (s, 1H), 7.81 (s,1H), 8.69 (s, 1H), 10.6 (br s, 1H). Resolution of the (R) and (S)enantiomers of the title compound is achieved by chiral HPLC using theChiralPak IA column with a 2:8 IPA/hexane mobile phase to giveenantiomer A (t_(r)=23.9 min) and enantiomer B (t_(r)=38.6 min).

4)5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid 2-isopropoxyethyl ester. MS (ESI) m/z 370.2 (M+H); NMR (400 MHz,CDCl₃) δ ppm 1.08 (d, J=6.1, 3 H); 1.10 (d, J=6.1, 3H), 2.58-2.78 (m,2H), 2.92-3.03 (m, 1H), 3.44-3.58 (m, 3H), 3.62-3.73 (m, 1H), 3.90 (s,3H), 4.14-4.23 (m, 1H), 4.35-4.44 (m, 1H), 6.57 (d, J=8.1 Hz, 1H), 6.84(s, 1H), 7.15 (d, J=1.3 Hz, 1H), 7.21 (dd, J=7.8, 1.3 Hz, 1H), 7.69 (s,1H).

5)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid 4-fluorobenzyl ester. MS (ESI) m/z 396.1, 398.1 (M+H); ¹H NMR (400MHz, CDCl₃) δ ppm 2.68-2.80 (m, 2H), 2.99-3.09 (m, 1H), 3.84-3.91 (m,1H), 5.22 (ABq, J=11.9 Hz, 2H), 6.56 (d, J=8.3 Hz, 1H), 6.92 (s, 1H),7.01-7.08 (m, 2H), 7.23-7.28 (m, 2H), 7.50 (dd, J=8.2, 1.6 Hz, 1H), 7.57(s, 1H), 7.70 (d, J=1.5 Hz, 1H). Resolution of the (R) and (S)enantiomers of the title compound is achieved by chiral HPLC usingChiralPak IA column and 3:7 i-PrOH/hexanes to give enantiomer A(t_(r)=39.2 min) and enantiomer B (t_(r)=60.3 min).

6)5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid 4-fluorobenzyl ester. MS (ESI) m/z 392.1 (M+H); ¹H NMR (400 MHz,CDCl₃) δ ppm 2.59 (ddd, J=13.0, 8.1, 3.0 Hz, 1H), 2.65-2.75 (m, 1H),2.92-3.00 (m, 1H), 3.55 (s, 3H), 3.61-3.71 (m, 1H), 5.15 (ABq, J=11.9Hz, 2H), 6:58 (d, J=7.8 Hz, 1H), 6.81 (s, 1H), 7.00-7.08 (m, 3H), 7.20(dd, J=8.0, 1.4 Hz, 1H), 7.23-7.29 (m, 2H), 7.47 (s, 1H).

Example 9 A.5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (4-fluorobenzyl)methylamide

Crude5-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (0.168 g, 0.59 mmol) is suspended in CH₂Cl₂ (3 mL) and cooled to 0°C. To it is added DMF (0.2 mL) followed by the addition of a CH₂Cl₂solution of oxalyl chloride (0.6 mL, 2.0 M). After 2 h,4-fluoro-N-methylbenzylamine (0.23 mL, 1.78 mmol) is added. The reactionis stirred for another 2 h, evaporated to dryness, and partitionedbetween EtOAc and saturated aqueous NaHCO₃. The organic phase is dried(Na₂SO₄), filtered, and concentrated. The crude residue is purified viaflash column chromatography (2-5% MeOH/CH₂Cl₂) to give5-(4-cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (4-fluorobenzyl)methylamide as a yellow solid. MS (ESI) m/z 405.2(M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 2.60 (s, 3H), 2.76-2.88 (m, 2H),2.95-3.04 (m, 1H), 3.57-3.69 (m, 1H), 3.74 (s, 3H), 4.43 (d, J=14.4 Hz,1H), 4.58-4.70 (m, 1H), 6.79 (s, 1H), 6.86-6.94 (m, 1H), 6.96-7.05 (m,2H), 7.10 (s, 1H), 7.19-7.25 (m, 3H), 7.55 (s, 1H). Resolution of the(R) and (S) enantiomers of the title compound is achieved by chiral HPLCusing ChiralPak AD column with a 6:4 EtOH/hexane mobile phase to giveenantiomer A (t_(r)=30.2 min) and enantiomer B (t_(r)=36.0 min).

Similarly prepared are the following:

1)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid ethylamide. MS (ESI) m/z 315.0, 317.0 (M+H); ¹H NMR (400 MHz,CDCl₃) (TFA salt) δ ppm 1.09 (t, J=7.2 Hz, 3H), 2.72-2.81 (m, 1H), 2.84(m, 1H), 3.15-3.27 (m, 2H), 3.32-3.42 (m, 1H), 4.12-4.22 (m, 1H), 6.81(d, J=8.1 Hz, 1H), 7.11 (s, 1H), 7.53 (obs d, J=7.3 Hz, 1H), 7.54 (s,1H), 7.78 (s, 1H) 9.52 (s, 1H).

2)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methylamide. MS (ESI) m/z 301.0, 303.0 (M+H); ¹H NMR (400 MHz,CDCl₃) (TFA salt) δ ppm 2.74-2.79 (obs m, 1H), 2.80 (d, J=4.6 Hz, 3H),2.85-2.94 (m, 1H), 3.19-3.28 (m, 1H), 4.13-4.22 (m, 1H), 6.83 (d, J=8.1Hz, 1H), 7.11 (s, 1H), 7.53 (dd, J=8.2, 1.4 Hz, 1H), 7.62 (br s, 1H),7.77 (d, J=1.5 Hz, 1H), 9.48 (s, 1H).

3)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid dimethylamide. MS (ESI) m/z 315.0, 317.0 (M+H); ¹H NMR (400 MHz,CDCl₃) (TFA salt) δ ppm 2.73 (s, 3H), 3.10 (s, 3H), 3.17-3.22 (m, 2H),3.35-3.44 (m, 2H), 3.52-3.62 (m, 2H), 7.15 (s, 1H), 7.42 (d, J=8.1 Hz,1H), 7.72 (dd, J=8.2, 1.6 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 8.61 (s, 1H).

4)3-Chloro-4-[5-(morpholino-4-carbonyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]benzonitrile.MS (ESI) m/z 356.9, 358.9 (M+H); ¹H NMR (400 MHz, CDCl₃) (TFA salt) δppm 2.97-3.64 (m, 8H), 3.74 (br s, 4H), 7.15 (s, 1H), 7.39-7.53 (m, 1H),7.71 (d, J=7.3 Hz, 1H), 7.85 (s, 1H), 8.66 (s, 1H).

5)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (2-methoxyethyl)methylamide. MS (ESI) m/z 359.0, 361.0 (M+H); ¹HNMR (400 MHz, CDCl₃) (HCl salt) δ ppm 2.78 (s, 3H), 2.98-3.12 (m, 1H),3.13-3.40 (m, 6H), 3.42-3.75 (m, 1H), 7.09 (s, 1H), 7.62 (br s, 1H),7.73 (s, 1H), 8.46 (s, 1H).

6)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (4-fluorobenzyl)methylamide. MS (ESI) m/z 409.2, 411.2 (M+H). MS(ESI) m/z 405.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 2.61 (br s, 3H),2.64-2.86 (m, 2H), 2.98-3.10 (m, 1H), 3.97-4.12 (m, 1H), 4.37-4.51 (m,1H), 4.68-4.84 (m, 1H), 6.63-6.77 (m, 1H), 6.91 (s, 1H), 7.01 (app t,J=8.6 Hz, 2H), 7.15-7.26 (m, 2H), 7.48-7.58 (m, 2H), 7.73 (br s, 1H).

7)5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (2-fluorobenzyl)methylamide. MS (ESI) m/z 405.1 (M+H); ¹H NMR (400MHz, CDCl₃) δ ppm 2.68 (br s, 3H), 2.72-2.92 (m, 2H), 3.00 (app dd,J=13.6, 7.8 Hz, 1H), 3.57-3.89 (m, 1H), 3.67 (s, 3H), 4.49-4.82 (m, 2H),6.77 (s, 1H), 6.91 (br s, 1H), 6.99-7.18 (m, 3H), 7.18-7.32 (m, 2H),7.43 (br s, 1H), 7.54 (br s, 1H).

8)5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (3-fluorobenzyl)methylamide. MS (ESI) m/z 405.1 (M+H); ¹H NMR (400MHz, CDCl₃) δ ppm 2.63 (br s, 3H), 2.73-2.84 (m, 1H), 2.84-2.93 (m, 1H),2.97-3.07 (m, 1H), 3.59-3.73 (m, 1H), 3.82 (br s, 3H), 4.44 (d, J=14.4Hz, 1H), 4.76 (m, 1H), 6.80 (s, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.96-7.07(m, 2H), 7.10-7.17 (m, 1H), 7.19-7.35 (m, 3H), 7.58 (s, 1H).

9)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (4-methoxybenzyl)methylamide. MS (ESI) m/z 421.1, 423.1 (M+H); NMR(400 MHz, CDCl₃) δ ppm 2.57 (br s, 3H), 2.60-2.77 (m, 2H), 2.95-3.06 (m,1H), 3.79 (s, 3H), 4.04-4.18 (m, 1H), 4.28-4.40 (m, 1H), 4.71-4.87 (m,1H), 6.54-6.66 (m, 1H), 6.78-6.90 (m, 4H), 7.10-7.20 (m, 1H), 7.38-7.53(m, 2H), 7.72 (br s, 1H). Resolution of the (R) and (S) enantiomers ofthe title compound is achieved by chiral HPLC using a ChiralPak IAcolumn and CH₃CN to give enantiomer A (t_(r)=25.9 min) and enantiomer B(t_(r)=403 min).

10)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid isobutylmethylamide. MS (ESI) m/z 357.1. 359.1 (M+H); ¹H NMR (400MHz, CDCl₃) δ ppm 0.87-0.93 (m, 6H), 1.95-2.12 (m, 1H), 2.59-2.80 (m,2H), 2.69 (s, 3H), 2.96-3.06 (m, 1H), 3.06-3.18 (m, 1H), 3.31-3.46 (m,1H), 3.95-4.12 (m, 1H), 6.61-6.75 (m, 1H), 6.88 (s, 1H), 7.53 (dd,J=8.2, 1.6 Hz, 1H), 7.60 (br s, 1H), 7.75 (s, 1H).

11)5-(2-Bromo-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid ethylamide. MS (ESI) m/z 359.0, 361.0 (M÷H); ¹H NMR (400 MHz,CDCl₃) δ ppm 1.17 (t, J=7.2 Hz, 3H), 2.54-4.68 (m, 1H), 2.86 (ddd,J=13.4, 8.1, 2.5 Hz, 1H), 2.99 (ddd, J=15.5, 9.0, 1.8 Hz, 1H), 3.33-3.45(m, 2H), 3.85-3.97 (m, 1H), 5.57 (app t, J=5.4 Hz, 1H), 6.60 (d, J=8.1Hz, 1H), 6.86 (s, 1H), 7.53 (s, 1H), 7.57 (dd, J=8.2, 1.6 Hz, 1H), 7.96(d, J=1.8 Hz, 1H).

12)5-(2-Bromo-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid cyclohexylmethylamide. MS (ESI) m/z 427.2, 429.2 (M+H); ¹H NMR (400MHz, CDCl₃) ppm 0.80-0.97 (m, 2H), 1.06-1.29 (m, 3H), 1.44-1.58 (m, 1H),1.57-1.76 (m, 5H), 2.56-2.70 (m, 1H), 2.83-2.94 (m, 1H), 2.94-3.03 (m,1H), 3.08-3.25 (m, 2H), 3.83-3.96 (m, 1H), 5.63 (t, J=5.7 Hz, 1H), 6.63(d, J=8.3 Hz, 1H), 6.85 (s, 1H), 7.49 (s, 1H), 7.57 (dd, J=8.2, 1.6 Hz,1H), 7.96 (d, J=1.5 Hz, 1H).

13)5-(2-Bromo-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (2,2,2-trifluoroethyl)amide. MS (ESI) m/z 413.0, 415.0 (M+H); ¹HNMR (400 MHz, CDCl₃) δ ppm 2.56-2.67 (m, 1H), 2.87 (ddd, J=13.3, 8.1,2.5 Hz, 1H), 3.01 (ddd, J=15.9, 8.8, 1.6 Hz, 1H), 3.78-3.92 (m, 1H),3.94-4.04 (m, 1H), 4.05-4.20 (m, 1H), 6.48 (d, J=8.3 Hz, 1H), 6.65 (s,1H), 7.05 (br s, 1H), 7.41 (s, 1H), 7.48 (dd, J=8.1, 1.5 Hz, 1H), 7.94(d, J=1.5 Hz, 1H).

14)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (2,2-dimethoxyethyl)amide. MS (ESI) m/z 375.1, 377.1 (M+H); ¹H NMR(400 MHz, CDCl₃) δ ppm 2.57-2.70 (m, 1H), 2.81 (ddd, J=13.3, 8.0, 2.4Hz, 1H), 2.95-3.05 (m, 1H), 3.30-3.36 (m, 1H), 3.36 (s, 3H), 3.38 (s,3H), 3.58 (ddd, J=13.8, 6.4, 4.8 Hz, 1H), 3.84-3.94 (m, 1H), 4.39 (t,J=4.9 Hz, 1H), J=5.7 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.85 (s, 1H), 7.54(dd, J=8.1, 1.8 Hz, 1H), 7.64 (s, 1H), 7.76 (d, J=1.5 Hz, 1H).

15)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (2-hydroxyethyl)amide. MS (ESI) m/z 331.2, 333.2 (M+H); ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.52-2.62 (m, 1H), 2.88 (dd, J=13.8, 8.7 Hz, 1H),3.05-3.15 (m, 1H), 3.21-3.30 (m, 1H), 3.34-3.49 (m, 2H), 3.71-3.84 (m,1H), 4.64 (t, J=5.3 Hz, 2H), 6.45 (d, J=8.1 Hz, 1H), 6.74 (s, 1H), 7.64(s, 1H), 7.85 (dd, J=8.2, 1.6 Hz, 1H), 8.02 (t, J=5.6 Hz, 1H), 8.16 (d,J=1.5 Hz, 1H).

16)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid amide. MS (ESI) m/z 287.3, 289.3 (M+H); ¹H NMR (400 MHz; DMSO-d₆) δppm 2.53-2.66 (m, 2H), 2.84-2.94 (m, 1H), 3.69-3.78 (m, 1H), 6.53 (d,J=8.1 Hz, 1H), 6.74 (s; 1H), 7.57 (s, 1H), 7.64 (s, 1H), 7.71 (s, 1H),7.84 (dd, J=8.2, 1.6 Hz, 1H), 8.17 (d, J=1.5 Hz, 1H).

17)3-Chloro-4-[5-(piperidine-1-carbonyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]benzonitrile.MS (ESI) m/z 355.3, 357.3 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.20 (brs, 2H), 1.60 (br s, 4H), 2.58-2.75 (m, 2H), 2.96-3.07 (m, 1H), 3.13-3.42(m, 3H), 3.84-4.02 (m, 1H), 3.99-4.12 (m, 1H), 6.71 (d, J=7.8 Hz, 1H),6:87 (s, 1H), 7.54 (dd, J=8.2, 1.6 Hz, 1H), 7.56 (s, 1H), 7.76 (d, J=1.5Hz, 1H).

18)3-Methoxy-4-[5-(piperidine-1-carbonyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl]benzonitrile.MS (ESI) m/z 351.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.58 (br s, 4H),1.88 (br s, 2H), 2.72-2.89 (m, 2H), 2.95-3.06 (m, 1H), 3.32 (br s, 4H),3.59-3.74 (m, 1H), 3.92 (s, 3H), 6.77 (s, 1H), 6.87-6.99 (m, 1H), 7.19(d, J=1.5 Hz, 1H), 7.24-7.30 (m, 1H), 7.54 (s, 1H).

19)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid cyclohexylmethylamide. MS (ESI) m/z 383.3, 385.3 (M+H); ¹H NMR (400MHz, CDCl₃) δ ppm 1.24-1.86 (m, 10H), 2.54 (s, 3H), 2.56-2.78 (m, 2H),2.93-3.11 (m, 1H), 3.15-3.32 (m, 1H), 3.98-4.16 (m, 1H), 6.63 (d, J=8.1Hz, 1H), 6.86 (s, 1H), 7.44-7.60 (m, 2H), 7.74 (s, 1H).

20)5-(2-Chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methylphenethylamide. MS (ESI) m/z 405.3, 407.3 (M+H); NMR (400MHz, CDCl₃) δ ppm 2.56 (br s, 3H), 2.60-2.76 (m, 2H), 2.79-3.25 (m, 3H),3.55 (d, J=10.4 Hz, 1H), 3.67-3.83 (m, 1H), 3.98-4.13 (m, 1H), 6.62 (d,J=7.8 Hz, 1H), 6.88 (s, 1H), 7.13-7.36 (m, 5H), 7.44 (br s, 1H), 7.50(d, J=7.8. Hz, 1H), 7.76 (br s, 1H).

21)5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (3-methoxybenzyl)methylamide. MS (ESI) m/z 417.4 (M+H); ¹H NMR (400MHz, CDCl₃) δ ppm 2.62 (br s, 3H), 2.76-2.88 (m, 1H), 2.88-2.99 (m, 1H),2.98-3.09 (m, 1H), 3.58-3.73 (m, 1H), 3.80 (s, 3H), 3.82 (br s, 3H),4.43-4.72 (m, 2H), 6.75-6.89 (m, 4H), 6.95 (d, J=7.6 Hz, 1H), 7.10-7.19(m, 1H), 7.24 (d, J=9.9 Hz, 2H), 7.62 (br s, 1H).

22)5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (4-methoxybenzyl)methylamide. MS (ESI) m/z 417.1 (M+H); ¹H NMR (400MHz, CDCl₃) δ ppm 2.59 (br s, 3H), 2.71-2.92 (m, 2H), 2.94-3.06 (m, 1H),3.58-3.70 (m, 1H), 3.75 (br s, 3H), 3.80 (s, 3H), 4.36-4.48 (m, 1H),4.54-4.72 (m, 1H), 6.78 (s, 1H), 6.81-6.95 (m, 3H), 7.11 (br s, 1H),7.14-7.27 (m, 3H), 7.53 (br s, 1H), Resolution of the (R) and (S)enantiomers of the title compound is achieved by chiral HPLC usingChiralPak AS-H column with a 3:7 EtOH/Heptane mobile phase to giveenantiomer A (t_(r)=28.9 min) and enantiomer B (t_(r)=92.3 min).

23)5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (2-methoxybenzyl)methylamide. MS (ESI) m/z 417.1 (M+H);

B.1,2,6′,7′-Tetrahydro-2-oxo-1-(2,2,2-trifluoroethyl)spiro[3H-indole-3,5′-[5H]pyrrolo[1,2-c]imidazole]-6-carbonitrile

A suspension of5-(2-Bromo-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (2,2,2-trifluoroethyl)amide (0.168 g, 0.405 mmol), given in example9, CuI (0.004 g, 0.021 mmol), N,N′-dimethylethylene diamine (0.005 mL,0.042 mmol), Cs₂CO₃ (0.198 g, 0.609 mmol), and THF (15 mL) is heated to110° C. for 60 h. The mixture is then filtered and concentrated. Theresidue is purified via flash chromatography (EtOAc/hexanes) to give1,2,6′,7′-Tetrahydro-2-oxo-1-(2,2,2-trifluoroethyl)spiro[3H-indole-3,5′-[5H]pyrrolo[1,2-c]imidazole]-6-carbonitrile.MS (ESI) m/z 333.1 (M+H); NMR (400 MHz, CDCl₃) δ ppm 2.85-2.96 (m, 1H),3.03-3.18 (m, 2H), 3.27-3.39 (m, 1H), 4.20-4.34 (m, 1H), 4.43-4.57 (m,1H), 6.86 (s, 1H), 7.04 (s, 1H), 7.30 (s, 1H), 7.35 (d, J=7.8 Hz, 1H),7.52 (dd, J=7.6, 1.3 Hz, 1H).

Similarly prepared are the following:

1)1-(Cyclohexylmethyl)-1,2,6′,7′-tetrahydro-2-oxospiro[3H-indole-3,5′-[5H]pyrrolo[1,2-c]imidazole]-6-carbonitrile.MS (ESI) m/z 347.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 0.99-1.14 (m,2H), 1.21 (d, J=9.3 Hz, 2H), 1.61-1.72 (m, 4H), 1.73-1.89 (m, 3H),2.79-2.91 (m, 1H), 2.99-3.15 (m, 2H), 3.27-3.37 (m, 1H), 3.58 (dd,J=7.5, 2.7 Hz, 2H), 6.84 (s, 1H), 7.02 (s, 1H), 7.16 (d, J=0.8 Hz, 1H),7.28 (d, J=7.6 Hz, 1H), 7.42 (dd, J=7.7, 1.4 Hz, 1H).

2)1-Ethyl-1,2,6′,7′-tetrahydro-2-oxospiro[3H-indole-3,5′-[5H]pyrrolo[1,2-c]imidazole]-6-carbonitrile.MS (ESI) m/z 279.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.34 (t, J=7.3Hz, 3H), 2.77-2.89 (m, 1H), 2.99-3.15 (m, 2H), 3.27-338 (m, 1H),3.73-3.90 (m, 2H), 6.85 (s, 1H), 7.06 (s, 1H), 7.19 (s, 1H), 7.29 (d,J=7.6 Hz, 1H), 7.43 (dd, J=7.6, 1.3 Hz, 1H).

Example 105-(4-Ethoxycarbonyl-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid

To a solution of5-(4-cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester (0.250 g, 0.877 mmol) in THF/EtOH (2:1, 21 mL) isadded an aqueous solution of LiOH (0.88 mL, 2 M) is added. After 2.5 hthe solution is concentrated and the resulting residue is purified byHPLC (2-23% MeCN/water containing 0.1% TFA). The title compound,5-(4-ethoxycarbonyl-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid, is isolated as a minor product. MS (ESI) m/z 319.0 (M+H).

Example 114-(5-Hydroxymethyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-methoxybenzonitrile

5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester (0.100 g, 0.336 mmol) is dissolved in THF (3 mL) andcooled to −10° C. A THF solution of lithium borohydride (0.08 mL, 2 M)is then added. The solution is removed from the cold bath and allowed towarm to room temperature before being heated to 40° C. at which timeadditional lithium borohydride (0.08 mL, 2 M) is added. The solution ismaintained at that temperature for 1.5 h before being allowed to cool toroom temperature and being quenched by the addition of 1 M HCl.Following aqueous workup the residue is warmed to 80° C. inethanolamine/CH₃CN (1:3) for 1 h. The solution is then concentrated andthe residue purified via prep HPLC (reversed phase; 5-100% CH₃CN/H₂O and0.1% TFA). Conversion to the free base provided4-(5-hydroxymethyl-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-methoxybenzonitrileas a white solid. MS (ESI) m/z 270.1 (M+H); ¹H NMR (400 MHz, CDCl₃) δppm 2.55-2.67 (m, 1H), 2.78-2.96 (m, 3H), 3.91 (s, 3H), 4.10 (d, J=11.6Hz, 1H), 4.46 (d, J=11.6 Hz, 1H), 6.57 (d, J=8.3 Hz, 1H), 6.73 (s, 1H),7.13-7.18 (obs m, 1H), 7.16 (s, 1H), 7.52 (s, 1H).

Example 12 A. 3-[3-(2-Bromobenzyl)-3H-imidazol-4-yl]propionic acidmethyl ester

To a solution of 3-(1-trityl-1H-imidazol-4-yl)propanoic acid methylester (5.0 g, 12.6 mmol) in CH₃CN (80 mL) is added a solution of2-bromobenzylbromide (2.84 g, 11.4 mmol) in CH₃CN (20 mL). The resultingclear solution is stirred at ambient temperature over the weekend. Themixture is concentrated and the remaining oil is taken up in 85 mLmethanol and heated up at 70° C. for 2 h. Then the mixture isconcentrated to give a yellow oil, which is taken up in EtOAc and washedwith saturated aqueous NaHCO₃ and brine, dried over anhydrous Na₂SO₄,and concentrated to yield a viscous oil. The crude reaction mixture issubjected to flash chromatography (silica gel) eluting with MeOH:CH₂Cl₂to give the desired compound. MS (ESI) m/z 323 (M+H).

B. 3-[3-(2-Bromobenzyl)-3H-imidazol-4-yl]propan-1-ol

To a solution of 3-[3-(2-bromobenzyl)-3H-imidazol-4-yl]propionic acidmethyl ester (1.89 g, 5.85 mmol) in MeOH at 0° C. is added NaBH₄ and theresulting mixture is stirred at 0° C. for 1 h and warmed up to ambienttemperature. The mixture is stirred at ambient temperature for 3 h andis quenched with saturated aqueous NH₄Cl, and is adjusted pH to 7 withsaturated aqueous Na₂CO₃. Then the reaction mixture is concentrated andextracted by CH₂Cl₂. The organic layer is washed with half saturatedaqueous NaCl, dried over anhydrous Na₂SO₄, and concentrated to yield awhite solid. MS (ESI) m/z 295 (M+H).

C. 1-(2-Bromobenzyl)-5-(3-chloropropyl)-1H-imidazole

To a solution of SOCl₂ (0.55 mL, 7.54 mmol) in CH₂Cl₂ (15 mL) at 0° C.is added 3-[3-(2-bromobenzyl)-3H-imidazol-4-yl]propan-1-ol in portionand the resulting white suspension is refluxed for 1.5 h. The mixture iscooled with ice and collected to give a buff-colored solid, which ispartitioned between CH₂Cl₂ and saturated aqueous NaHCO₃. The organiclayer is washed with brine, dried over anhydrous Na₂SO₄, andconcentrated to give an oil. MS (ESI) m/z 313 (M+H).

D. 5-(2-Bromophenyl)-5,6,7,8,-tetrahydro-imidazo[1,5-a]pyridine

To a slurry of 1-(2-bromobenzyl)-5-(3-chloropropyl)-1H-imidazole (0.662g, 2.12 mmol) and TMEDA (0.683 mL, 4.55 mmol) in THF (10 mL) at −78° C.is added LDA (1.8 M in heptane/THF/ethylbenzene, 2.5 mL, 4.5 mmol) andthe yellow clear solution is stirred at −78° C. After 3.5 hr, thereaction is quenched by saturated aqueous NH₄Cl, and the mixture ispartitioned between EtOAc and saturated aqueous NaHCO₃. The organiclayer is washed with brine, dried and concentrated to give an oil, whichis subjected to flash chromatography (silica gel) eluting withMeOH:CH₂Cl₂ to yield the desired compound. MS (ESI) m/z 277 (M+H).

Similarly prepared is:

5-(4-Bromophenyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine. MS (ESI)m/z 277 (M+H).

The following compound is prepared in a similar fashion using LHMDS (1.0M in THF) as base instead of LDA for the cyclization:5-(2-Bromo-4-fluorophenyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine. MS(ESI) m/z 295 (M+H).

From the material outlined in Example 2J above, the procedure above gavethe cyclized material:5-(2-Bromophenyl)-8-methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine. MS(ESI) m/z 291 (M+H).

Example 13 A.5-(2-Thiophen-2-yl-phenyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine

To a solution of5-(2-bromophenyl)-5,6,7,8,-tetrahydro-imidazo[1,5-a]pyridine, Example12D (120 mg, 0.43 mmol) in DME (2 mL) is added thiophene-2-boronic acid(166 mg, 1.3 mmol), aqueous Na₂CO₃ (2M, 1.0 mL, 2.0 mmol), and Pd(PPh₃)₄(20 mg). The reaction mixture is refluxed overnight. The mixture ispartitioned between EtOAc and 1M NaOH. The organic layer is washed bysat. NaHCO₃, dried and concentrated to give an oil. The crude reactionmixture is subjected to flash chromatography (silica gel) eluting withacetone:hexane to yield the desired compound. MS (ESI) m/z 280 (M+H); ¹HNMR (400 MHz, CDCl₃) δ ppm 1.58-1.74 (m, 1H), 1.85-2.01 (m, 2H),2.14-2.27 (m, 1H), 2.74-2.94 (m, 2H), 5.45 (dd, J=8.6, 5.1 Hz, 1H), 6.81(s, 1H), 7.00-7.05 (m, 2H), 7.06 (s, 1H), 7.10 (dd, J=5.3, 3.5 Hz, 1H),7.31-7.37 (m, 2H), 7.39 (dd, J=5.2, 1.1 Hz, 1H), 7.41-7.46 (m, 1H).

B. 5-(2-Thiophen-3-yl-phenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine

Thereafter, in a similar fashion, is also prepared the followingcompound except for the Suzuki coupling procedure:

To a solution of5-(2-bromophenyl)-5,6,7,8,-tetrahydroimidazo[1,5-a]pyridine (95 mg,0.343 mmol) in DME (2 mL) is added thiophene-3-boronic acid (53 mg,0.414 mmol), aqueous Na₂CO₃ (2M, 0.5 mL, 1.0 mmol), and Pd(PPh₃)₄ (20mg). The reaction mixture is run under microwave irradiation at 120° C.for 20 min. The mixture is partitioned between EtOAc and brine. Theorganic layer is washed by brine, dried over Na₂SO₄ and concentrated togive an oil. The crude reaction mixture is subjected to flashchromatography eluting with acetone:hexane to yield the desiredcompound. MS (ESI) m/z 280 (M+H).

Similarly prepared are the following:

1) 5-Biphenyl-2-yl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine. MS (ESI)m/z 275 (M+H).

2) 5-(2-Furan-2-yl-phenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine. MS(ESI) m/z 264 (M+H).

The following compounds are prepared in a similar fashion except usingPS-PPh₃-Pd(0) resin instead of Pd(PPh₃)₄ for the Suzuki couplingreaction:

3) 5-(4′-Fluorobiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 293 (M+H); ¹H NMR (400 MHz, MeOD) δ ppm 1.55-1.76 (m, 1H),1.86-2.07 (m, 2H), 2.06-2.26 (m, 1H), 2.68-3.01 (m, 2H), 5.32 (dd,J=8.6, 5.1 Hz, 1H), 6.78 (s, 1H), 6.99-7.09 (m, 1H), 7.17-7.29 (m, 3H),7.29-7.38 (m, 1H), 7.38-7.51 (m, 4H).

Similarly, following the same Suzuki coupling procedure is prepared:

4)5-(4′-Trifluoromethylbiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 343 (M+H).

5) 5-(4′-Methoxybiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 305 (M+H).

6) 5-(2′-Chlorobiphenyl-211)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 309, 311 (M+H).

7) 5-(3′-Chlorobiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 309, 311 (M+H); ¹H NMR (400 MHz, MeOD) δ ppm 1.47-1.74 (m,1H), 1.84-2.03 (m, 2H), 2.08-2.23 (m, 1H), 2.71-2.99 (m, 2H), 5.30 (dd,J=8.6, 5.3 Hz, 1H), 6.78 (s, 1H), 7.00-7.10 (m, 1H), 7.24 (s, 1H),7.27-7.39 (m, 2H), 7.41-7.47 (m, 3H), 7.47-7.53 (m, 2H).

8) 5-(4′-Chlorobiphenyl-2-yl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine.MS (ESI) m/z 309, 311 (M+H); ¹H NMR (400 MHz, MeOD) δ ppm 1.51-1.70 (m,1H), 1.81-2.01 (m, 2H), 2.03-2.21 (m, 1H), 2.66-2.96 (m, 2H), 5.29 (dd,J=8.5, 5.2 Hz, 1H), 6.75 (s, 1H), 6.95-7.07 (m, 1H), 7.19 (s, 1H),7.25-7.32 (m, 1H), 7.34-7.44 (m, 4H), 7.44-7.54 (m, 2H).

9)5-(3′,5′-Dichlorobiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 343, 345, 347 (M+H).

10)5-(3′,5′-Difluorobiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 311 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.49-1.70 (m, 1H),1.76-1.90 (m, 1H), 1.90-2.00 (m, 1H), 2.02-2.16 (m, 1H), 2.68-2.83 (m,1H), 2.88 (dt, J=16.2, 5.1 Hz, 1H), 5.15 (dd, J=9.1, 5.1 Hz, 1H), 6.81(s, 1H), 6.82-6.91 (m, 3H), 7.05 (s, 1H), 7.06-7.10 (m, 1H), 7.20-7.26(m, 1H), 7.32-7.41 (m, 2H).

11)5-(3′,5′-Dimethylbiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 303 (M+H).

12)5-(3′-Chloro-4′-fluorobiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 327, 329 (M+H).

13)5-(3′,4′-Dichlorobiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 343, 345, 347 (M+H).

14)5-(4′-isopropylbiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 317 (M+H).

15) 5-(2′-Fluorobiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 293 (M+H).

16)5-(2′-Methoxybiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine. MS(ESI) m/z 305 (M+H).

17)N,N-Dimethyl-[2′-(5,6,7,8-tetrahydrolmidazo[1,5-a]pyridin-5-yl)-biphenyl-4-yl]amine.MS (ESI) m/z 318 (M+H).

18)5-(2′-Trifluoromethylbiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 343 (M+H).

19) 5-(2′-Methylbiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 289 (M+H).

20) 5-(2′-Ethoxybiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 319 (M+H).

21)5-(2′-Methoxymethyl-biphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 319 (M+H).

By analogy to the compounds described above the following are preparedfrom5-(2-Bromo-4-fluorophenyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine,given as example 12D:

1) 5-(5-Fluorobiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 293 (M+H). Resolution of the (R) and (S) enantiomers of thetitle compound is achieved by chiral HPLC using the ChiralPak AD columnwith a IPA/hexanes mobile phase to give enantiomer A and enantiomer B.For enantiomer B: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.42-1.67 (m, 1H),1.76-1.88 (m, 1H), 1.88-1.97 (m, 1H), 2.01-2.13 (m, 1H), 2.65-2.80 (m,1H), 2.86 (dt, J=15.9, 5.1 Hz, 1H), 5.13 (dd, J=9.5, 4.9 Hz, 1H), 6.78(s, 1H), 6.97-7.02 (m, 1H), 7.02-7.10 (m, 3H), 7.28-7.36 (m, 2H),7.36-7.49 (m, 3H).

2)5-(5,4′-Difluorobiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 311 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.33-1.60 (m, 1H),1.66-1.79 (m, 1H), 1.79-1.91 (m, 1H), 1.90-2.03 (m, 1H), 2.60-2.73 (m,1H), 2.79 (dt, J=16.2, 4.6 Hz, 1H), 5.01 (dd, J=9.6, 4.8 Hz, 1H), 6.72(s, 1H), 6.89 (dt, J=9.1, 1.5 Hz, 1H), 6.92-7.00 (m, 3H), 7.01-7.13 (m,2H), 7.16-7.24 (m, 2H).

3)5-(5,2′-Difluorobiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 311 (M+H).

4)5-(2′-Chloro-5-fluorobiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 327 (M+H).

5)5-(4-Fluoro-2-thiophen-3-yl-phenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 299 (M+H): ¹H NMR (400 MHz, CDCl₃) δ ppm 1.58-1.68 (m, 1H),1.74-2.02 (m, 2H), 2.05-2.22 (m, 1H), 2.67-2.82 (m, 1H), 2.88 (dt,J=16.2, 4.8 Hz, 1H), 5.24 (dd, J=9.2, 4.9 Hz, 1H), 6.80 (s, 1H),6.99-7.06 (m, 4H), 7.08 (dd, J=4.9, 1.1 Hz, 1H), 7.21 (dd, J=2.9, 1.1Hz, 1H), 7.43 (dd, J=4.8, 3.0 Hz, 1H).

C. 5-(2-Pyridin-3-yl-phenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine

The following compound is prepared in a similar fashion using themodified Suzuki coupling procedure:

To a solution of5-(2-bromophenyl)-5,6,7,8,-tetrahydroimidazo[1,5-a]pyridine (89 mg,0.321 mmol) in dioxane (2 mL) is added pyridine-3-boronic acid1,3-propanediol cyclic ester (105 mg, 0.644 mmol), K₃PO₄ (105 mg, 0.707mmol), and PS-PPh₃Pd (O) resin (0.13 mmol/g, 100 mg). The reactionmixture is run on a microwave at 130° C. for 20 min. The mixture ispartitioned between EtOAc and brine. The organic layer is washed withbrine, dried over Na₂SO₄ and concentrated to give an oil. The crudereaction mixture is subjected to flash chromatography (silica gel)eluting with MeOH:CH₂Cl₂ to yield the desired compound. MS (ESI) m/z 275(M+H).

Similarly prepared are the following:

1) 5-(2-Pyridin-4-yl-phenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.MS (ESI) m/z 275 (M+H)

2)2′-(5,6,7,8-Tetrahydroimidazo[1,5-a]pyridine-5-yl)biphenyl-2-carbonitrile.MS (ESI) m/z 300 (M+H).

D. (R) and (S)-5-Biphenyl-2-yl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine

Resolution of the enantiomers of the title compound is achieved bychiral HPLC using the ChiralPak AD column with a 25% IPA/Hexane mobilephase to give enantiomer A (t_(r)=5.3 min) and enantiomer B (t_(r)=8.1min). For enantiomer B: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.59 (m,1H), 1.64-1.87 (m, 2H), 1.90-2.12 (m, 1H), 2.72 (t, J=6.2 Hz, 2H), 5.23(dd, J=8.0, 5.2 Hz, 1H), 6.65 (s, 1H), 6.81-6.95 (m, 1H), 7.12 (s, 1H),7.20-7.28 (m, 1H), 7.34-7.40 (m, 2H), 7.40-7.44 (m, 3H), 7.44-7.52 (m,2H).

Similarly resolved are the following:

1) (R) and(S)-5-(2′-Chlorobiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine

ChiralPak AD column with a 20% IPA/Hexane mobile phase to giveenantiomer A (t_(r)=7.0 min) and enantiomer B (t_(r)=8.8 min).

2) (R) and(S)-5-(2′-Trifluoromethylbiphenyl-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine

ChiralPak AS column with a 10% IPA/Hexane mobile phase to giveenantiomer A (t_(r)=15 min) and enantiomer B (t_(r)=21 min). Forenantiomer B: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.45-1.54 (m, 1H), 1.78-1.90(m, 1H), 1.90-1.98 (m, 1H), 1.99-2.09 (m, 1H), 2.67-2.81 (m, 1H),2.81-2.92 (m, 1H), 4.74 (dd, J=10.1, 4.5 Hz, 1H), 6.78 (s, 1H), 7.08 (s,1H), 7.16 (d, J=7:6 Hz, 1H), 7:20-7.28 (m, 1H), 7.30-7.43 (m, 3H), 7.52(t, J=7.6 Hz, 1H), 7.58 (t, J=7.1 Hz, 1H), 7.80 (d, J=7.6 Hz, 1H).

E. 5-(2-Cyclopropylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine

From 5-(2-bromophenyl)-5,6,7,8,-tetrahydro-imidazo[1,5-a]pyridine,Example 12D, is converted to the title compound according to the methodoutlined in Tet. Lett. 2002, 43, 6987. MS (ESI) m/z 239 (M+H); ¹H NMR(400 MHz, CDCl₃) δ ppm 0.78 (br s, 2H), 1.02 (br s, 2H), 1.79 (br s,1H), 2.00 (br s, 3H), 2.31 (br s, 1H), 2.84-2.97 (m, 2H), 5.83 (dd,J=7.6, 5.3 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.85 (s, 1H), 7.09-7.13 (m,2H), 7.15 (t, J=7.3 Hz, 1H), 7.23 (t, J=7.3 Hz, 1H).

Similarly prepared from5-(4-Bromophenyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine is:5-(4-Cyclopropylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine, MS(ESI) m/z 239 (M+H); ¹H NMR (400 MHz, MeOD) δ ppm 0.68 (br s, 2H), 0.96(br s, 2H), 1.71-1.83 (m, 1H), 1.87-2.04 (m, 3H), 2.22-2.33 (m, 1H),2.81-2.94 (m, 2H), 5.26 (dd, J=7.8, 5.1 Hz, 1H), 6.74 (s, 1H), 7.00 (d,J=8.3 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H), 7.14 (br s, 1H).

F. 5-Biphenyl-2-O-8-methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine

To a solution of5-(2-bromophenyl)-8-methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine(573 mg, 1.97 mmol) in DME (10 mL) is added phenylboronic acid (480 mg,3.94 mmol), aqueous Na₂CO₃ (2M, 4 mL, 8.0 mmol), and Pd(PPh₃)₄ (500 mg).The reaction mixture is stirred at reflux overnight. The mixture ispartitioned between EtOAc and brine. The organic layer is washed bybrine, dried over Na₂SO₄ and concentrated to give an oil, which issubjected to flash chromatography (silica gel) eluting with MeOH:CH₂Cl₂to yield the desired compound. MS (ESI) m/z 289 (M+H)

Resolution of the stereoisomers of the title compound is achieved bychiral HPLC using the ChiralPak AD column with a 15% IPA/Hexane mobilephase to give isomer A (t_(r)=7.8 min), isomer B (t_(r)=9.9 min), isomerC (t_(r)=17 min) and isomer D (t_(r)=24 min). For isomer B: ¹H NMR (400MHz, CDCl₃) δ ppm 1.35 (d, J=6.8 Hz, 3H), 1.45-1.58 (m, 1H), 1.63-1.74(m, 1H), 1.84-2.00 (m, 2H), 2.88-3.00 (m, 1H), 5.41 (t, J=5.4 Hz, 1H),6.68 (d, J=7.3 Hz, 1H), 6.86 (s, 1H), 7.15 (s, 1H), 7.20-7.51 (m, 8H).

Example 14 A.6-[5-(3-Hydroxypropyl)-imidazol-1-ylmethyl]phenyl-4-carbonitrile

To a solution of3-bromo-4-[5-(3-hydroxypropyl)-imidazol-1-ylmethyl]benzonitrile (1.02 g,3.2 mmol) that is prepared by alkylation of imidazole from Example 21with bromide described in Example 1C followed by removal of the silylprotecting group by analogy to the first step in Example 3C in DME (10mL) is added phenylboronic acid (586 mg, 4.8 mmol), aqueous Na₂CO₃ (2M,4.8 mL, 9.6 mmol), and PS-PPh₃-Pd (O) resin (0.13 mmol/g, 1 g). Thereaction mixture is run in a microwave at 130° C. for 20 min. Themixture is partitioned between EtOAc and brine. The organic layer iswashed with brine, dried over Na₂SO₄ and concentrated to give oil.

B. 6-[5-(3-Chloropropyl)-imidazol-1-ylmethyl]biphenyl-3-carbonitrile

To a solution of SOCl₂ (0.382 mL, 5.24 mmol) in CH₂Cl₂ (20 mL) at 0° C.is added6-[5-(3-hydroxypropyl)imidazol-1-ylmethyl]biphenyl-3-carbonitrile inportion and the resulting white suspension is refluxed for 1.5 h. Themixture is cooled in ice and partitioned between CH₂Cl₂ and saturatedaqueous NaHCO₃. The organic layer is washed with brine, dried overanhydrous Na₂SO₄ and concentrated to give an oily foam.

C.6-(5,6,7,8-Tetrahydroimidazo[1,5-a]pyridin-5-yl)-biphenyl-3-carbonitrile

To a solution of6-[5-(3-chloropropyl)imidazol-1-ylmethyl]biphenyl-3-carbonitrile (1.0 g,3.0 mmol) in THF (16 mL) at 0° C. is added t-BuOK/THF (1.0 M, 6 mL, 6.0mmol). The mixture is warmed up to ambient temperature and stirred for 2h. The reaction mixture is quenched by saturated aqueous NH₄Cl andpartitioned between CH₂Cl₂ and brine. The organic layer is washed bybrine, dried over anhydrous Na₂SO₄ and concentrated to give the crudeoil, which is subjected to flash chromatography (silica gel) elutingwith MeOH:CH₂Cl₂ to yield the desired compound. MS (ESI) m/z 300 (M+H);¹H NMR (400 MHz, CDCl₃) δ ppm 1.50-1.66 (m, 1H), 1.73-1.83 (m, 1H),1.83-1.95 (m, 1H), 1.95-2.16 (m, 1H), 2.68-2.95 (m, 2H), 5.28 (dd,J=8.5, 5.2 Hz, 1H), 6.83 (s, 1H), 7.01-7.15 (m, 2H), 7.27-7.35 (m, 2H),7.43-7.54 (m, 3H), 7.58 (s, 1H), 7.62 (d, J=8.3 Hz, 1H). Resolution ofthe enantiomers of the title compound is achieved by Chiral HPLC usingthe ChiralPak AD column with a 20% IPA/Hexane mobile phase.

Example 15 A.3-Bromo-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrile

4-{5-[3-Hydroxypropyl]imidazol-1-ylmethyl}-3-bromobenzonitrile isconverted to the corresponding chloride according to Example 14B. Theresulting chloride is treated with a base, such as t-BuOK as in Example14C above, to effect cyclization to the title compound. MS (ESI) m/z302.1, 304.1 (M+H); ¹H NMR (400 MHz, MeOD) δ ppm 1.74-1.85 (m, 2H),2.08-2.17 (m, 1H), 2.34-2.43 (m, 1H), 2.82-2.91 (m, 1H), 2.93-3.00 (m,1H), 5.88 (t, J=5.6 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 6.82 (d, J=1.0 Hz,1H), 7.34 (s, 1H), 7.69 (dd, J=8.1, 1.5 Hz, 1H), 8.09 (d, J=1.5 Hz, 1H).

Similarly prepared are the following:

1)3-Fluoro-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrileMS (ESI) m/z 242.1 (M+H); ¹H NMR (400 MHz, MeOD) (HCl salt) δ ppm1.88-1.98 (m, 1H), 2.02-2.11 (m, 1H), 2.14-2.24 (m, 1H), 2.39-2.47 (m,1H), 2.92-3.00 (m, 1H), 3.02-3.09 (m, 1H), 5.83 (dd, J=9.1, 5.3 Hz, 1H),7.37-7.39 (m, 1H), 7.42 (dd, J=10.4, 8.8 Hz, 1H), 7.67 (dd, J=6.8, 2.0Hz, 1H), 7.86-7.90 (m, 1H), 8.65 (s, 1H). Resolution of the (R) and (S)enantiomers of the title compound is achieved by chiral HPLC usingChiralPak AS-H column and 30 IPA:hexane to give enantiomer A (t_(r)=24min) and enantiomer B (t_(r)=30 min).

2)3-Chloro-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrileMS (ESI) m/z 258.1, 260.1 (M+H); ¹H NMR (400 MHz, MeOD) 5 ppm 1.74-1.85(m, 2H), 2.07-2.17 (m, 1H), 2.33-2.44 (m, 1H), 2.81-2.91 (m, 1H),2.91-3.00 (m, 1H), 5.92 (d, J=5.3 Hz, 1H), 6.76 (dd, J=8.1 Hz, 1H), 6.82(s, 1H), 7.35 (s, 1H), 7.65 (dd, J=8.1, 1.5 Hz, 1H), 7.89-7.95 (m, 1H).

3)3-Methoxy-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrileMS (ESI) m/z 254.1 (M+H); ¹H NMR (400 MHz, MeOD) (HCl salt) δ ppm1.85-1.95 (m, 1H), 1.95-2.04 (m, 1H), 2.18-2.28 (m, 1H), 2.31-2.41 (m,1H), 2.99 (s, 2H), 3.88-3.94 (m, 3H), 5.85-5.92 (m, 1H), 7.09 (d, J=7.8Hz, 1H), 7.32-7.41 (m, 2H), 7.48 (s, 1H), 8.53 (s, 1H).

B.3-Methyl-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrile

3-Bromo-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrile,prepared above, is converted to the corresponding toluene by the methodoutlined in Tet. Lett. 2000, 41, 6237. MS (ESI) m/z 238.1 (M+H); ¹H NMR(400 MHz, MeOD) δ ppm 1.77-1.89 (m, 2H), 1.91-2.00 (m, 1H), 2.29-2.39(m, 1H), 2.45 (s, 3H), 2.86-2.93 (m, 2H), 5.71 (t, J=6.1 Hz, 1H), 6.77(d, J=8.1 Hz, 1H), 6.81 (s, 1H), 7.29 (s, 1H), 7.49 (d, J=8.1 Hz, 1H),7.61 (s, 1H).

C.3-Cyclopropyl-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrile

3-Bromo-4-(5,6,7,8-tetrahydro-imidazo[1,5-a]pyridin-5-yl)benzonitrile,prepared above, is converted to the corresponding cyclopropane by themethod outlined in Tet. Lett. 2002, 43, 6987. MS (ESI) m/z 264.1 (M+H);¹H NMR (400 MHz, MeOD) δ ppm 0.69-0.80 (m, 2H), 0.94-1.06 (m, 2H),1.69-1.80 (m, 2H), 1.93-2.04 (m, 2H), 2.24-2.34 (m, 1H), 2.76-2.86 (m,2H), 5.95 (d, J=6.1 Hz, 1H), 6.64-6.72 (m, 2H), 7.15 (s, 1H), 7.35 (s,1H), 7.39 (d, J=8.1 Hz, 1H).

Example 175-(Cyano-phenyl)-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine-5-carboxylicacid methyl ester

¹H NMR (400 MHz, CDCl₃) δ ppm 1.67-1.77 (m, 2H), 2.10-2.17 (m, 1H),2.78-2.88 (m, 3H), 3.83 (s, 3H), 6.87 (s, 1H), 7.11 (d, J=8.3 Hz, 2H),7.46 (s, 1H), 7.64 (d, J=8.3 Hz, 2H).

Example 184-((R)-1-Bromo-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile

To (R)-4-(5,6,7,8-Tetrahydroimidazo[1,5-a]yridine-5-yl)benzonitrile (1.2g, 5.4 mmol) in acetonitrile (50 mL) at 0° C. is added NBS (0.96 g, 5.4mmol). The reaction is stirred until complete consumption of thestarting material (about 2 h) before concentrating under reducedpressure. The residue is partitioned between CH₂Cl₂ and brine. Theseparated organic phase is washed with fresh brine (2×), dried (Na₂SO₄),and concentrated under reduced pressure. The residue is purified byflash chromatography eluting with 2.5% MeOH in CH₂Cl₂. The resultingfoam is diluted with CH₂Cl₂ and HCl (g) is bubbled through for 10 min.The product is isolated by concentrating under reduced pressure. ¹H NMR(400 MHz, MeOD) (HCl salt) δ ppm 1.88-1.99 (m, 1H), 2.01-2.17 (m, 2H),2.34-2.50 (m, 1H), 2.80-2.95 (m, 2H), 5.64 (dd, J=8.6, 5.1 Hz, 1H), 7.50(d, J=8.3 Hz, 2H), 7.80 (d, J=8.3 Hz, 2H), 8.54 (s, 1H).

Example 18 A. 3-[3-(2-Bromobenzyl)-3H-Imidazol-4-yl]-3-methylbutan-1-ol

To a solution of4-[3-(tert-butyldimethylsilanyloxy)-1,1-dimethylpropyl]-1-trityl-1H-imidazole(650 mg, 1.27 mmol) in CH₃CN (10 mL) at ambient temperature is added asolution of 2-bromobenzyl bromide (420 mg, 1.68 mmol) in CH₃CN (10 mL).The resulting solution is stirred at 80° C. for 6 h. The mixture iscooled to ambient temperature and diethylamine (2 mL) is added, followedby MeOH (10 mL) and the mixture is heated at 75° C. for 1 hr and stirredat ambient temperature overnight. To the reaction mixture is addedHCl/dioxane (4 M, 5 mL, 20 mmol) and stirred at ambient temperature for1 h. The mixture is neutralized with saturated aqueous NaHCO₃ andconcentrated. The residue is partitioned between CH₂Cl₂ and brine. Theorganic layer is washed with brine, dried over Na₂SO₄ and concentratedto give an oil, which is subjected to flash chromatography (silica gel)eluting with MeOH:CH₂Cl₂ to yield the desired compound. MS (ESI) m/z 323(M+H).

B. 1-(2-Bromobenzyl)-5-(3-chloro-1,1-dimethylpropyl)-1H-imidazole

By analogy to Example 14B, the title compound is prepared from alcohol18A. MS (ESI) m/z 341 (M+H).

C.5-(2-Bromophenyl)-8,8-dimethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine

Compound 16B is cyclized according to the procedure outlined in 14C. MS(ESI) m/z 305 (M+H).

D. 5-Biphenyl-2-yl-8,8-dimethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine

The title compound is prepared from the bromide 16C by the methoddescribed in Example 13A. MS (ESI) m/z 303 (M+H); ¹H NMR (400 MHz,CDCl₃) 5 ppm 1.40 (s, 3H), 1.44 (s, 3H), 1.59-1.74 (m, 1H), 1.76-1.92(m, 1H), 2.12-2.32 (m, 2H), 5.19-5.35 (m, 1H), 6.94-7.05 (m, 1H), 7.22(s, 1H), 7.29-7.34 (m, 2H), 7.34-7.40 (m, 1H), 7.40-7.52 (m, 5H), 7.89(s, 1H).

Example 19 A.6-(5-Methyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)biphenyl-3-carbonitrile

To a solution of6-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)biphenyl-3-carbonitrile(53 mg, 0.177 mmol) in THF (2 mL) at −40° C. is added LHMDS (1.0 M inTHF, 0.27 mL, 0.27 mmol). The resulting brown solution is stirred at−30° C. for 0.5 h. To the reaction mixture is added methyl iodide (0.017mL, 0.272 mmol) and the mixture is warmed up to ambient temperature andstirred overnight. The reaction mixture is quenched by saturated aqueousNH₄Cl and the reaction is partitioned between CH₂Cl₂ and brine. Theorganic layer is washed with brine, dried over anhydrous Na₂SO₄ andconcentrated to give the crude oil, which is subject to flashchromatography (silica gel) eluting with MeOH:CH₂Cl₂ to yield thedesired compound. MS (ESI) m/z 314 (M+H).

Similarly prepared is:

6-(5-Allyl-5,6,7,5-tetrahydroimidazo[1,5-a]pyridine-5-yl)biphenyl-3-carbonitrile.

6-(5-Allyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-5-yl)biphenyl-3-carbonitrileis prepared from6-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)biphenyl-3-carbonitrileand allyl bromide by analogy to 19A above. MS (ESI) m/z 340 (M+H); ¹HNMR (400 MHz, CDCl₃) δ ppm (HCl salt) 1.73-1.98 (m, 2H), 2.02-2.16 (m,1H), 2.23-2.38 (m, 1H), 2.54-2.65 (m, 1H), 2.68-2.83 (m, 1H), 2.86-3.02(m, 1H), 3.00-3.14 (m, 1H), 5.11 (d, J=17.2 Hz, 1H), 5.23 (d, J=10.1 Hz,1H), 5.44-5.69 (m, 1H), 6.87 (d, J=7.3 Hz, 1H), 6.92 (s, 1H), 7.02-7.12(m, 1H), 7.13-7.22 (m, 1H), 7.27-7.39 (m, 3H), 7.45 (d, J=2.0 Hz, 1H),7.71 (dd, J=8.5, 1.9 Hz, 1H), 8.31 (s, 1H).

B.6-(5-n-Propyl-5,6,7,8-tetrahydro-imidazo[1,8-a]pyridine-5-yl)biphenyl-3-carbonitrile

To a solution of6-(5-allyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-5-yl)biphenyl-3-carbonitrile(35′ mg, 0.103 mmol) in EtOH (2 mL) at ambient temperature is addedH₂NNH₂/THF (1.0 M, 15 mL, 15 mmol) and saturated aqueous CuSO₄ (0.1 mL).The reaction mixture is stirred at ambient temperature overnight. Themixture is concentrated and dissolved in EtOAc, which is washed withwater, dried over anhydrous Na₂SO₄ and concentrated to give the crudeoil, which is subjected to flash chromatography (silica gel) elutingwith MeOH:CH₂Cl₂ to yield the desired compound. MS (ESI) m/z 342 (M+H);¹H NMR (400 MHz, CDCl₃) δ ppm (HCl salt) 0.95 (t, J=7.2 Hz, 3H),1.21-1.33 (m, 2H), 1.80-1.90 (m, 2H), 1.90-2.02 (m, 1H), 2.09-2.37 (m,3H), 2.59-2.68 (m, 1H), 2.71-2.85 (m, 1H), 6.81-6.88 (m, 1H), 6.90-6.98(m, 2H), 7.19-7.25 (m, 1H), 7.27-7.39 (m, 3H), 7.43 (d, J=1.8 Hz, 1H),7.71 (dd, J=8.3, 2.0 Hz, 1H), 8.10-8.18 (m, 1H).

Example 20 cis- andtrans-3-Fluoro-4-[7-(4-fluorobenzyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl]benzonitrile

The ester obtained in Example 2G (5.0 g, 12.6 mmol) is driedazeotropically with toluene and then dissolved in THF (20 mL). Thissolution is added dropwise to a solution of LHMDS (1M in hexanes, 15.7mL, 15.7 mmol) in THF (20 mL) at −75° C. (dry ice-acetone bath). After10 min, 4-fluorobenzyl bromide (3.57 g, 18.9 mmol) is added dropwise.The mixture is stirred at −75° C. for 4 h, whereupon 10% aqueous aceticadd is added and the cooling bath is removed. After extraction withethyl acetate, the organic phase is dried over Na₂SO₄ and concentratedin vacuo. Purification by silica gel chromatography (ethylacetate=hexanes, 85:15) afforded the product as oil.

The ester obtained above (2.15 g, 4.26 mmol) is dissolved in THF (15 mL)and cooled to −20° C. LiAlH₄ (1M in THF, 10.7 mL, 10.7 mmol) is addedand the cooling bath is removed. After 1 h at room temperature,saturated aqueous NaHCO₃ is carefully added. After extraction with ethylacetate, the organic phase is dried over Na₂SO₄ and concentrated invacuo to afford the product as oil.

The alcohol obtained above (3.6 g, 7.56 mmol), TBSCl (1.25 g, 8.31mmol), DMAP (0.092 g, 0.756 mmol) and imidazole (1.54 g, 22.6 mmol) aredissolved in DMF (10 mL) and heated to 75° C. for 4 h. After dilutingwith ethyl acetate, the mixture is washed three times with water. Theorganic phase is dried over Na₂SO₄ and concentrated in vacuo to affordthe product as an oil.

The silyl ether obtained above (2.0 g, 3.38 mmol) and2-fluoro-4-cyanobenzyl bromide (0.94 g, 4.40 mmol) are dissolved inacetonitrile (10 mL) and refluxed overnight. After cooling to roomtemperature methanol (5 mL) is added and the mixture is refluxed for 3h, whereupon the volatiles are removed in vacuo. The residue is purifiedby silica gel chromatography (dichloromethane-methanol, 19:1) to affordthe product as an oil.

The alcohol obtained above (0.65 g, 1.70 mmol) is dissolved in carbontetrachloride (5 mL) and thionyl chloride (0.51 g, 4.29 mmol) is added.The mixture is refluxed for 1.5 h, cooled to room temperature andquenched with saturated aqueous NaHCO₃. The aqueous phase is extractedwith dichloromethane. The combined organic phase is dried over Na₂SO₄and concentrated in vacuo. Purification by silica gel chromatography(dichloromethane-methanol, 19:1) afforded the product as an oil.

The chloride obtained above (0.46 g, 1.20 mmol) is dissolved in THF (45mL) and cooled to 0° C. Potassium tert-butoxide (1.0M in THF, 4.8 mL,4.8 mmol) is added dropwise and after another 30 min, 1.0% aqueousacetic acid is added. After extraction with ethyl acetate, the organicphase is dried over Na₂SO₄ and concentrated in vacuo. Purification bysilica gel chromatography (dichloromethane-methanol, 9:1) afforded theclean cis isomer and a mixture of cis and trans isomers. The clean transisomer is obtained by preparative HPLC purification of the mixture. MS(ESI) m/z 350 (M+H); For cis isomer, ¹H NMR (400 MHz, MeOD) δ ppm1.64-1.73 (m, 1H), 2.05-2.20 (m, 2H), 2.35 (dd, J=15.0, 12.8 Hz, 1H),2.65 (d, J=6.8 Hz, 2H), 2.81-2:88 (m, 1H), 5.40 (dd, J=11.5, 4.9 Hz,1H), 6.61 (s, 1H), 6.87-6.96 (m, 2H), 7.05 (s, 1H), 7.09-7.18 (m, 2H),7.35 (t, J=7.6 Hz, 1H), 7.47-7.57 (m, 2H); For trans isomer, ¹H NMR (400MHz, MeOD) δ ppm 1.85-2.13 (m, 3H), 2.39 (dd, J=16.0, 11.0 Hz, 1H),2.49-2.61 (m, 2H), 2.87 (dd, J=16.0, 4.7 Hz, 1H), 5.90 (dd, J=5.2, 3.4Hz, 1H), 6.40 (t, J=7.8 Hz, 1H), 6.71 (s, 1H), 6.81-6.90 (m, 2H),6.95-7.01 (m, 2H), 7.38 (dd, J=8.1, 1.3 Hz, 1H), 7.40 (s, 1H), 7.47-7.50(d, J=10.2, 1.3 Hz, 1H).

Similarly prepared is the following:

trans-3-Methoxy-4-[7-(4-fluorobenzyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl]benzonitrile.MS (ESI) m/z 362 (M+H); ¹H NMR (400 MHz, CDCl₃) (TFA salt) δ ppm1.88-2.12 (m, 3H), 2.40 (dd, J=16.0, 9.6 Hz, 1H), 2.54 (dd, J=13.6, 7.6Hz, 1H), 2.63 (dd, J=13.6, 6.1 Hz, 1H), 2.89 (dd, J=16.0, 4.4 Hz, 1H),3.89 (s, 3H), 5.80 (dd, J=5.3, 3.0 Hz, 1H), 6.26 (d, J=7.8 Hz, 1H), 6.82(s, 1H), 6.88-7.04 (m, 4H), 7.09-7.16 (m, 2H), 7.22 (s, 1H).

Example 21 A,3-Bromo-4-{4-[4-(tert-butyldimethylsilanyloxy)butyl]imidazol-1-ylmethyl}benzonitrile

To 4-[4-(tert-butyldimethylsilanyloxy)butyl]-1-trityl-1H-imidazole (3.95g, 7.95 mmol) is added acetonitrile (300 mL). To this solution is added3-bromo-4-bromomethylbenzonitrile (2.14 g, 7.78 mmol). The solution isstirred at 40° C. for 18 h. The solvent is then removed in vacuo andmethanol (300 ml) is added. The solution is heated to 55° C. and stirredfor 1.5 h. Saturated sodium bicarbonate is then added and stirred for 10min. The organic solvent is removed in vacuo, and the crude productextracted into ethyl acetate and washed with water. The organic solventis removed in vacuo to give the crude product. Chromatography (silicagel, 1:0 to 1:1 to 0:1 hexanes:ethyl acetate) gives the pure product. MS(ESI) m/z 448, 450 (M+H).

Following this protocol is also prepared:

1)3-Chloro-4-{4-[4-(tert-butyldimethylsilanyloxy)butyl]-imidazol-1-ylmethyl}benzonitrile.MS (ESI) m/z 404, 406 (M+H).

2)3-Methoxy-4-{4-[4-(tert-butyldimethylsilanyloxy)butyl]-imidazol-1-ylmethyl}benzonitrile.MS (ESI) m/z 400 (M+H).

3)3-Fluoro-4-{4-[4-(tert-butyldimethylsilanyloxy)butyl]-imidazol-1-ylmethyl}benzonitrile.MS (ESI) m/z 388 (M+H).

4)2-Bromo-4-{5-[4-tert-butyldimethylsilanyloxy)butyl]-imidazol-1-ylmethyl}benzonitrile.MS (ESI) m/z 448,450 (M+H).

5)1-(2-Bromo-4-Fluorobenzyl)-5-[4-tert-butyldimethylsilanyloxy)butyl]-1H-imidazole.MS (ESI) m/z 441, 443 (M+H).

6)1-2-Bromo-benzyl-5-[4-(tert-butyldimethylsilanyloxy)-butyl]-1H-imidazole.MS (ESI) m/z 423, 425 (M+H).

7)3-Bromo-4-[(5-(4-tert-butyldimethylsilanyloxy)-1-methylbutylimidazol-1-ylmethyl-]benzonitrile.MS (ESI) m/z 462, 464 (M+H).

8)3-Bromo-4-{5-[4-(tert-butyldimethylsilanyloxy)butyl]-imidazol-1-ylmethyl}benzoicacid methyl ester. MS (ESI) m/z 481, 484 (M+H).

Example 22 3-Bromo-4-[5-(4-chlorobutyl)-imidazol-1-ylmethyl]benzonitrile

To3-bromo-4-{4-[4-tert-butyldimethylsilanyloxybutyl]-imidazol-1-ylmethyl}-benzonitrile(1.09 g, 2.4 mmol) is added methanol (100 ml). To this solution is addedhydrogen chloride, as a 4 M solution in dioxane (1.0 ml, 4.0 mmol). Thesolution is stirred 30 minutes. The solvent is then removed in vacuo togive the product as the hydrogen chloride salt. The product is extractedinto methylene chloride and washed with saturated sodium bicarbonate.The organic phase is taken and the solvent removed in vacuo to give theintermediate alcohol as the free base. To this intermediate is addedmethylene chloride (100 ml). To this solution is added thionyl chloride(1.0 ml, 13.6 mmol) at room temperature. The solution is heated to 40°C. and stirred 3 h. The solution is allowed to cool, and the solvent andexcess thionyl chloride is removed in vacuo. The resulting solid isextracted into methylene chloride and washed with saturated sodiumbicarbonate. The organic phase is taken and removed in vacuo to give theproduct. MS (ESI) m/z 352, 354, 356 (M+H).

Following this protocol is also prepared:

1) 3-Chloro-4-[5-(4-chlorobutyl)imidazol-1-ylmethyl]benzonitrile. MS(ESI) m/z 308, 310, 312 (M+H).

2) 3-Methoxy-4-[5-(4-chlorobutyl)imidazol-1-ylmethyl]benzonitrile. MS(ESI) m/z 304, 306 (M+H).

3). 3-Fluoro-4-[5-(4-chlorobutyl)-imidazol-1-ylmethyl]benzonitrile. MS(ESI) m/z 292, 294 (M+H).

4) 2-Bromo-4-[5-(4-chlorobutyl)imidazol-1-ylmethyl]benzonitrile. MS(ESI) m/z 352, 354, 356 (M+H).

5)3-Bromo-4-{5-(4-chloro-1-methylbutyl)-imidazol-1-ylmethyl}benzonitrile.MS (ESI) m/z 366, 368, 370 (M+H).

6) 1-(2-Bromobenzyl)-5-(4-chlorobutyl)-1H-imidazole. MS (ESI) m/z 327,329, 331 (M+H).

7) 1-(2-Bromo-4-fluorobenzyl)-5-(4-chlorobutyl)-1H-imidazole. MS (ESI)m/z 345, 347, 349 (M+H).

8) 3-Bromo-4-[5-(4-chlorobutyl)imidazol-1-ylmethyl]benzoic acid methylester. MS (ESI) m/z 385, 387, 389 (M+H).

Example 233-Bromo-4-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzonitrile

To 3-Bromo-4-[5-(4-chlorobutyl)imidazol-1-ylmethyl]benzonitrile (0.672g, 1.9 mmol) is added anhydrous THF (40 mL). The solution isdeoxygenated with nitrogen bubbled through it for 15 minutes. A solutionof potassium t-butoxide in THF (3.41 ml, 1M, 3.41 mmol) is added. Thereaction is allowed to proceed for 2 h at room temperature. The reactionis then quenched by the addition of methanol (3 mL) followed by aqueousammonium chloride. The product is extracted into ethyl acetate andwashed with saturated sodium bicarbonate. The organic layer is removedin vacuo to give crude product. Chromatography (reverse phase HPLC,gradient 1:9 acetonitrile:water to 7:3 acetonitrile:water, over 8minutes, pH 2) gives the pure product. MS (ESI) m/z 316, 318 (M+H)

Resolution of the (R) and (S) enantiomers of the title compound isachieved by chiral HPLC using the ChiralPak IA column with a 20%IPA:hexane mobile phase to give enantiomer A (t_(r)=24.0 min) andenantiomer B (t_(r)=29 minutes).

Similarly prepared are the following:

1)3-Fluoro-4-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzonitrile.MS (ESI) m/z 256 (M+H).

Resolution of the (R) and (S) enantiomers of the above compound isachieved by chiral HPLC using the ChiralPak IA column with a 20%IPA:hexane mobile phase to give enantiomer A (t_(r)=18.2 min) andenantiomer B (t_(r)=20.3 minutes). For enantiomer A: ¹H NMR (400 MHz,CDCl₃) δ ppm 1.38-1.67 (m, 2H), 1.72-1.93 (m, 2H), 1.96-2.14 (m, 1H),2.44-2.74 (m, 2H), 2.97 (dd, J=15.4, 6.3 Hz, 1H), 5.73 (dd, J=6.1, 2.8Hz, 1H), 6.80-6.94 (m, 2H), 7.23 (s, 1H), 7.39-7.42 (m, 1H), 7.43 (s,1H).

2)3-Chloro-4-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzonitrileMS (ESI) m/z 272, 274 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.50-1.87 (m,4H), 1.97-2.19 (m, 1H), 2.42-2.61 (m, 1H), 2.67-2.85 (m, 1H), 2.85-3.00(m, 1H), 5.71 (dd, J=7.2, 2.7 Hz, 1H), 6.83 (s, 1H), 6.98 (s, 1H), 7.17(d, J=8.1 Hz, 1H), 7.56 (dd, J=8.1, 1.5 Hz, 1, H), 7.72 (d, J=1.5 Hz,1H).

Resolution of the (R) and (S) enantiomers of the above compound isachieved by chiral HPLC using the ChiralPak IA column with a 20%IPA:hexane mobile phase to give enantiomer A (t_(r)=24.0 min) andenantiomer B (t_(r)=29.0 minutes).

3)3-Bromo-4-(9-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzonitrileMS (ESI) m/z 330, 332 (M+H).

4)2-Bromo-4-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzonitrile.MS (ESI) m/z 316, 318 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.39-1.57 (m,2H), 1.73-1.96 (m, 2H), 2.04-2.17 (m, 1H), 2.18-2.37 (m, 1H), 2.47-2.73(m, 1H), 2.81-3.03 (m, 1H), 5.50-5.70 (m, 1H), 6.90 (s, 1H), 6.93-7.00(m, 1H), 7.29 (s, 1H), 7.35 (s, 1H), 7.65 (d, J=8.1 Hz, 1H).

Example 24 5-(2-Bromophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine

To 5-(2-bromophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine (1.65g, 4.75 mmol) is added anhydrous THF (100 mL). Nitrogen is bubbledthrough this solution for 15 minutes and LHMDS (10 mL, 1.0 M, 10 mmol)is added. The reaction is allowed to proceed for 2 h at roomtemperature. The reaction is then quenched by the addition of methanol(5 mL) followed by aqueous ammonium chloride. The product is extractedinto ethyl acetate and washed with saturated sodium bicarbonate. Theorganic layer is removed in vacuo to give the crude product.Chromatography (reverse phase HPLC, gradient 1:9 acetonitrile:water to7:3 acetonitrile:water, over 8 minutes, pH 2) gives the pure product. MS(ESI) m/z 291, 293 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.54-1.67 (m,1H), 1.70-1.83 (m, 1H), 1.83-1.96 (m, 2H), 2.12-2.23 (m, 1H), 2.27-2.40(m, 1H), 2.77-2.87 (m, 1H), 2.91-3.01 (m, 1H), 5.58 (dd, J=8.5, 1.9 Hz,1H), 6.81 (s, 1H), 6.82 (s, 1H), 7.20-7.29 (m, 2H), 7.33-7.41 (m, 1H),7.64 (dd, J=8.1, 1.3 Hz, 1H).

Similarly prepared are the following:

1)5-(2-Bromo-4-fluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine.MS (ESI) m/z 309, 311 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.54-1.63 (m,1H), 1.72-1.94 (m, 3H), 2.10-2.33 (m, 2H), 2.75-2.97 (m, 2H), 5.53 (d,J=8.3 Hz, 1H), 6.78 (s, 1H), 6.81 (s, 1H), 7.01-7.13 (m, 1H), 7.16-7.28(m, 1H), 7.40 (dd, J=8.1, 2.5 Hz, 1H).

2) 3-Bromo-4-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzoicacid methyl ester. MS (ESI) m/z 349, 351 (M+H).

3)3-Methoxy-4-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzonitrile.MS (ESI) m/z 268 (M+H).

Example 25 4%Fluoro-6-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)biphenyl-3-carbonitrile

To3-bromo-4-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzonitrile(0.507 g, 1.59 mmol) is added DME (7.0 mL). To this is added aqueous 2Msodium carbonate (3.0 mL, 6 mmol) followed by 4-fluorophenylboronic acid(0.552 g, 3.97 mmol). This mixture is transferred to a microwave safevial. Tetrakis(triphenylphosphine) palladium(0) (0.03 g, 0.025 mmol) isadded, and the vessel sealed. The mixture is stirred briefly (30seconds) and placed in a microwave for 25 minutes at 125° C. The vial isallowed to cool and unsealed. The mixture is extracted into ethylacetate and washed with saturated sodium bicarbonate. The organic layeris removed in vacuo. The resulting material is subjected tochromatography (Silica gel, 1:50 to 1:25 methanol:methylene chloride) togive the desired product. MS (ESI) m/z 332 (M+H)

Resolution of the (R) and (S) enantiomers of the title compound isachieved by chiral HPLC using the ChiralPak IA column with a 20%IPA:hexane mobile phase to give enantiomer A (t_(r)=17.6 min) andenantiomer B (t_(r)=23.0 minutes). For enantiomer, A: ¹H NMR (400 MHz,CDCl₃) δ ppm 1.40-1.57 (m, 2H), 1.77-1.92 (m, 2H), 1.94-2.04 (m, 2H),2.43 (dd, J=15.0, 9.7 Hz, 1H), 2.85 (dd, J=15.4, 7.3 Hz, 1H), 5.13 (dd,J=7.5, 3.2 Hz, 1H), 6.83 (s, 1H), 6.92 (s, 1H), 7.01-7.12 (m, 4H), 7.51(d, J=8.3 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.75 (dd, J=8.1, 1.8 Hz, 1H).

Similarly prepared are the following:

1) 5-Biphenyl-2-yl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine. MS (ESI)m/z 289 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.35-1.56 (m, 2H),1.80-1.89 (m, 1H), 1.89-1.98 (m, 1H), 1.99-2.08 (m, 2H), 2.28-2.41 (m,1H), 2.87 (dd, J=15.3, 6.2 Hz, 1H), 5.05-5.15 (m, 1H), 6.80 (br s, 1H),6.97 (br s, 1H), 7.03-7.10 (m, 2H), 7.31-7.36 (m, 4H), 7.40-7.48 (m,3H).

Resolution of the (R) and (S) enantiomers of the above compound isachieved by chiral HPLC using the ChiralPak AS column with a 20%IPA:hexane mobile phase to give enantiomer A (t_(r)=7.5 min) andenantiomer B (t_(r)=10.8 minutes).

2) 5-(4′-Fluorobiphenyl-2-yl)6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepineMS (ESI) m/z 307 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.34-1.56 (m, 2H),1.81-1.99 (m, 2H), 2.02-2.09 (m, 2H), 2.28-2.41 (m, 1H), 2.89 (dd,J=15.2, 6.6 Hz, 1H), 4.98-5.05 (m, 1H), 6.79 (s, 1H), 6.90 (s, 1H), 7.02(d, J=7.6 Hz, 4H), 7.28-7.34 (m, 1H), 7.39-7.52 (m, 3H).

Resolution of the (R) and (S) enantiomers of the above compound isachieved by chiral HPLC using the ChiralPak AS column with a 15%IPA:hexane mobile phase to give enantiomer A (t_(r)=9.3 min) andenantiomer B (t_(r)=11.6 minutes).

3)5-(2′-Chlorobiphenyl-2-yl)6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine.MS (ESI) m/z 323, 325 (M+H).

4)2′-(6,7,8,9)-Tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)biphenyl-4-carbonitrile.MS (ESI) m/z 314 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.33-1.58 (m, 2H),1.84-1.96 (m, 1H), 1.96-2.16 (m, 3H), 2.26-2.38 (m, 1H), 2.92 (dd,J=15.3, 6.7 Hz, 1H), 4.90-4.97 (m, 1H), 6.83 (s, 1H), 6.94 (s, 1H), 7.17(d, J=7.6 Hz, 2H), 7.28-7.37 (m, 1H), 7.45-7.57 (m, 3H), 7.65 (d, J=8.3Hz, 2H).

5)5-(2′-Trifluoromethylbiphenyl-2-yl)6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepineMS (ESI) m/z 357 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.27-1.39 (m, 1H),1.41-1.55 (m, 1H), 1.86-1.95 (m, 1H), 1.97-2.13 (m, 3H), 2.14-2.25 (m,1H), 2.84 (dd, J=15.4, 6.1 Hz, 1H), 4.61 (d, J=9.9 Hz, 1H), 6.80 (s,1H), 6.87 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.37(t, J=7.6 Hz, 1H), 7.44-7.51 (m, 2H), 7.56 (d, J=3.8 Hz, 2H), 7.78 (d,J=8.1 Hz, 1H).

6)5-(3′-Nitrobiphenyl-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine.MS (ESI) m/z 334 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.34-1.58 (m, 2H),1.84-1.93 (m, 1H), 1.95-2.17 (m, 3H), 2.25-2.36 (m, 1H), 2.90 (dd,J=15.3, 6.7 Hz, 1H), 4.97 (dd, J=9.1, 1.5 Hz, 1H), 6.81 (s, 1H), 6.91(s, 1H), 7.23-7.28 (m, 1H), 7.34-7.38 (m, 1H), 7.45-7.57 (m, 4H), 8.07(t, J=1.9 Hz, 1H), 8.18-8.25 (m, 1H).

7)5-(5-Fluorobiphenyl-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine.MS (ESI) m/z 307 (M+H).

8)4′-Fluoro-6-(9-methyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)biphenyl-3-carbonitrile.MS (ESI) m/z 346 (M+H).

Resolution of the (R)(R), (R)(S), (S)(R), and (S)(S) isomers of theabove compound is achieved by chiral HPLC using the ChiralPak IA columnwith a 15% IPA:hexane mobile phase to give isomer A (t_(r)=18.1 min),isomer B (t_(r)=21.8 minutes), isomer C (t_(r)=24.8 minutes) and isomerD=27.5 minutes). For isomer D: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.31-1.35(m, 1H), 1.40 (d, J=6.8 Hz, 3H), 1.64-1.77 (m, 1H), 1.91-2.00 (m, 1H),2.10-2.23 (m, 2H), 2.26-2.34 (m, 1H), 2.51-2.60 (m, 1H), 5.24 (d, J=10.1Hz, 1H), 6.94-7.02 (m, 2H), 7.08-7.15 (m, 3H), 7.70 (d, J=1.8 Hz, 1H),7.77 (d, J=8.1 Hz, 1H), 7.85 (s, 1H), 7.89 (dd, J=8.2, 1.6 Hz, 1H).

9)3-(3,5-Dimethylisoxazol-4-yl)-4-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzonitrile.MS (ESI) m/z 333 (M+H)

10)3-Pyridin-4-yl-4-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzonitrile.MS (ESI) m/z 315 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37-1.63 (m, 2H),1.77-1.95 (m, 2H), 1.96-2.10 (m, 2H), 2.35-2.52 (m, 1H), 2.86 (dd,J=15.5, 7.2 Hz, 1H), 5.04-5.13 (m, 1H), 6.85 (s, 1H), 6.89 (s, 1H),6.98-7.07 (m, 2H), 7.58 (d, J=8.1 Hz, 1H), 7.64 (d, J=1.5 Hz, 1H), 7.82(dd, J=8.3, 1.8 Hz, 1H), 8.67 (d, J=6.1 Hz, 2H).

11)3-Pyridin-3-yl-4-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzonitrile.MS (ESI) m/z 315 (M+H); ¹H NMR (400 MHz, CDCl₃) (HCl salt) δ ppm1.41-1.63 (m, 2H), 1.70-1.93 (m, 2H), 1.95-2.13 (m, 2H), 2.29-2.54 (m,1H), 2.84 (dd, J=15.4, 7.3 Hz, 1H), 5.11 (t, J=5.1 Hz, 1H), 6.82 (s,1H), 6.90 (s, 1H), 7.28-7.39 (m, 2H), 7.55 (d, J=8.3 Hz, 1H), 7.64 (d,J=1.5 Hz, 1H), 7.80 (dd, J=8.1, 1.8 Hz, 1H), 8.39-8.53 (m, 1H), 8.68 (t,J=3.3 Hz, 1H).

12)5-(6,7,8,9-Tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)biphenyl-2-carbonitrile.MS (ESI) m/z 314 (M+H).

Example 264-(5-Allyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)-3-bromobenzonitrile

To4-(6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)-3-bromobenzonitrile(0.330 g, 1.04 mmol) is added anhydrous tetrahydrofuran (60 mL).Nitrogen is bubbled through the solution for 15 minutes. LDA in THF (2.2mL, 1.0M, 2.2 mmol) is added at room temperature. The reaction isallowed to stir for 15 min at room temperature. Allyl bromide (12.78 g,90.6 mmol) is then added. The reaction is allowed to stir for anadditional 5 min. The reaction is then quenched by the addition ofmethanol (2 mL) followed by aqueous ammonium chloride. The product isextracted into ethyl acetate and washed with saturated aqueous sodiumbicarbonate. The organic layer removed in vacuo to give crude product.Chromatography (silica gel, methanol:methylene chloride, gradient 0%methanol to 5% methanol over 30 minutes gives the pure product. MS (ESI)m/z 356, 358 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.35-1.52 (m, 2H),1.67-1.77 (m, 1H), 1.84-2.00 (m, 3H), 2.82 (dd, J=15.3, 5.7 Hz, 1H),3.15-3.41 (m, 3H), 5.14-5.30 (m, 2H), 5.67-5.82 (m, 1H), 6.26 (d, J=8.1Hz, 1H), 6.86 (s, 1H), 7.45 (dd, J=8.3, 1.8 Hz, 1H), 7.79 (s, 1H), 7.94(d, J=1.8 Hz, 1H).

Similarly prepared are the following:

1)3-Chloro-(5-ethyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)benzonitrile.MS (ESI) m/z 300, 302 (M+H); ¹H NMR (400 MHz, CDCl₃) δ ppm 1.07 (t,J=7.3 Hz, 3H), 1.24-1.52 (m, 2H), 1.60-1.79 (m, 1H), 1.86-2.07 (m, 3H),2.19-2.44 (m, 1H), 2.50-2.62 (m, 1H), 2.84 (dd, J=15.4, 5.8 Hz, 1H),3.18 (dd, J=14.8, 5.7 Hz, 1H), 6.21 (d, J=8.3 Hz, 1H), 6.88 (s, 1H),7.40 (dd, J=8.5, 1.9 Hz, 1H), 7.65 (s, 1H), 7.71 (d, J=1.8 Hz, 1H).

2)6-(5-Ethyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)-4′-fluorobiphenyl-3-carbonitrile.MS (ESI) m/z 360 (M+H).

3)6-(5-Methyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)-4′-fluorobiphenyl-3-carbonitrile.MS (ESI) m/z 346 (M+H).

Example 273′-Methylene-2′,3′,6,7,8,9-hexahydrospiro[imidazo[1,5-a]azepine-5,1′-indene]-5′-carbonitrile

To4-(5-allyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepin-5-yl)-3-bromobenzonitrile(0.275 g, 0.76 mmol) is added DME (3.0 mL). To this solution is addedaqueous 2M sodium carbonate (1.5 ml, 3.0 mmol) followed by4-fluorophenylboronic acid (0.269 g, 1.92 mmol). This mixture istransferred to a microwave safe vial Tetrakis(triphenylphosphine)palladium(0) (0.04 g, 0.034 mmol) is added, and the vessel sealed. Themixture is stirred briefly (30 seconds) and place in a microwave for 25minutes at 130° C. The vial is allowed to cool and unsealed. The mixtureis extracted with ethyl acetate and washed with saturated aqueous sodiumbicarbonate. The separated organic layer is concentrated in vacuo. Theresulting material is subjected to two sequential chromatographyprocedures (1: Silica gel, 1:50 to 1:25 methanol:methylene chloride. 2:Reverse phase HPLC, gradient 10-95% % Acetonitrile:Water, pH2, over 8minutes) to give the product. MS (ESI) m/z 276 (M+11); ¹H NMR (400 MHz,CDCl₃) δ ppm 1.47-1.61 (m, 1H), 1.85-1.99 (m, 1H), 2.01-2.16 (m, 3H),2.25-2.36 (m, 1H), 2.63 (t, 1H), 2.99 (d, J=16.4 Hz, 1H), 3.10 (dd,J=15.5, 5.7 Hz, 1H), 3.23-3.32 (m, 1H), 5.21-5.25 (m, 1H), 5.62-5.67 (m,1H), 6.50 (s, 1H), 6.78 (s, 1H), 7.54-7.58 (m, 1H), 7.66-7.70 (m, 1H),7.88 (s, 1H).

Example 287-Benzyl-5-(3,5-dimethoxy-phenyl)-6,7,8,9-tetrahydro-5H-Imidazo[1,5-a]azepine

A. 3-(1-trityl-1H-imidazol-4-yl)propionaldehyde

To a solution of DMSO (3.57 g, 45.6 mmol) in dichloromethane (100 mL) at−78° C. under nitrogen is added oxalyl chloride (2.0M in DCM, 17.1 mL,34.2 mmol). After 20 min at −78° C., the alcohol prepared in step 2(8.41 g, 22.82 mmol) in dichloromethane (30 mL) is cannulated dropwise.After 30 min at −78° C., triethylamine (9.24 g, 91.3 mmol) is addeddropwise and the mixture is allowed to warm to room temperature. Themixture is diluted with diethyl ether (800 mL) and washed with saturatedaqueous ammonium chloride (2×200 mL) and brine (200 mL). The combinedorganic phase is dried over magnesium sulfate and filtered. Afterconcentration in vacuo, the product is obtained as an orange gum.

B. 4-but-3-enyl-1-trityl-1H-imidazole

tert-BuOK (5.78 g, 51.53 mmol) is dissolved in THF (80 mL) and added toa suspension of methyltriphenylphosphonium bromide (20.00 g, 56.00 mmol)in THF (120 mL) at 0° C. under nitrogen. After 30 min at 0° C., thealdehyde obtained in step 3 (8.5 g) in THF (40 mL) is cannulateddropwise. The cooling bath is removed and after 1 h, the mixture isdiluted with ethyl acetate (800 mL) and washed with saturated aqueousammonium chloride (400 mL) and brine (400 mL). The combined organicphase is dried over magnesium sulfate and filtere. The residue ispurified by silica gel flash chromatography (elution with hexanes-ethylacetate, 1:1) to give the alkene (6.72 g) as a pale yellow solid.

C.(E)-1-(3,5-dimethoxyphenyl)-5-(1-trityl-1H-imidazol-4-yl)pent-2-en-1-one

Toluene (100 mL) is added to (PPh₃)₂Pd(BnCl) (0.151 g, 0.199 mmol) and3,5-dimethoxybenzoyl chloride (4.00 g, 19.94 mmol) under nitrogen,followed with tributylvinyltin (6.11 g, 21.93 mmol). The yellow solutionis heated to 80° C., to give a paler yellow solution. After 1.5 h, themixture is partially concentrated and poured onto a column of 10% wt KFin silica gel. Elution with hexanes then hexanes-ethyl acetate 10 to 15%gave 1-(3,5-dimethoxyphenyl)propenone (3.57 g) as pale yellow oil.

A portion (1.32 g, 6.86 mmol) is added to a solution of the alkeneprepared above (1.00 g, 2.74 mmol) in dichloromethane (25 mL).p-Toluenesulfonic acid (0.574 g, 3.018 mmol) is added, the solution isdegassed by bubbling nitrogen for 25 min, and it is then refluxed for 30min. After cooling, second generation Grubbs' catalyst (0.116 g, 0.137mmol) is added and the purple solution is heated to reflux. After 45min, the mixture is cooled, diluted with ether and washed with saturatedaqueous sodium bicarbonate and brine. After drying over MgSO₄ andfiltering, silica gel (2 g) is added and the mixture is concentrated invacuo. The residue is absorbed on a pad of silica gel in a sinteredfunnel, followed by elution with ethyl acetate-hexanes, 1:1 to 4:1. Thefiltrate is concentrated in vacuo to give a residue which is purified byflash silica gel chromatography (hexanes-ethyl acetate, 1:1 to 3:7) toafford the product as a brown gum.

D.3-benzyl-1-(3,5-dimethoxyphenyl)-5-(1-trityl-1H-imidazol-4-yl)pentan-1-one

Zinc foil (0.556 g, 8.512 mmol) is cut in small pieces and covered withTHF (0.5 mL) in a dry flask under nitrogen. Dibromoethane (0.132 g,0.704 mmol) is added and the flask is gently heated with a heat gun fortwo minutes, whereupon TMSCl (0.039 g, 0.355 mmol) is added. The mixtureis stirred at room temperature for 10 min and benzyl bromide (passedthrough a plug of alumina, 1.20 g, 7.04 mmol) in THF (2 mL) is addeddropwise over 10 min. The colorless mixture is stirred for another 2 hand a portion (1.87 M assumed based on 85% yield and 3.2 mL measuredvolume, 2.00 mL, 3.74 mmol) is added to a solution of CuCN (0.231 g,2.580 mmol) and LiCl (dried at 150° C. under vacuum for 2 h, 0.234 g,5.512 mmol) in THF (15 mL) at −78° C. The mixture is warmed to −20° C.,stirred at this temperature for 5 min and recooled to −78° C. TMSCl(0.68 g, 5.28 mmol) is added, followed with the ketone prepared in above(0.620 g, 1.173 mmol) in THF (10 mL) over 10 min to give a yellowslurry. After 3 h, the mixture is place in a −25° C. bath (cryobath) andstirred at this temperature for 30 h, whereupon it is diluted withether, quenched with 10% v/v aqueous ammonia-aqueous saturated ammoniumchloride, and stirred vigorously for 15 min. The organic layer is washedwith brine. After drying over MgSO₄, filtering and concentrating invacuo, the residue (0.63 g) is taken up in ether (100 mL) and stirredwith aqueous 1 M HCl for 5 min. The organic phase is separated, washedwith saturated aqueous sodium bicarbonate, brine and dried over MgSO₄.After drying over MgSO₄ and filtering, the mixture is concentrated invacuo to give the crude product.

E.3-Benzyl-1-(3,5-dimethoxyphenyl)-5-(1-trityl-1H-imidazol-4-yl)pentan-1-ol

The crude ketone prepared above (0.53 g, 0.854 mmol) is dissolved indichloromethane (4 mL) and methanol (8 mL), and sodium borohydride(0.129 g, 3.415 mmol) is added. After 30 min, water (25 mL) is added andthe volatiles are evaporated in vacuo. The aqueous phase is extractedwith dichloromethane and the combined organic phase is dried over MgSO₄,filtered through a cotton plug and concentrated in vacuo. Purificationby silica gel flash chromatography (elution with hexanes-ethyl acetate,1:1 to 3:7) afforded the alcohol as white foam and a 1:1 mixture ofdiastereomers.

F.7-Benzyl-5-(3,5-dimethoxy-phenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine

The alcohol prepared above (0.150 g, 0.241 mmol) is dissolved indichloromethane (10 mL) and thionyl chloride (0.100 g, 0.843 mmol) isadded. After 30 min, 10 drops of saturated aqueous sodium bicarbonateare added. The mixture is dried over MgSO₄, filtered and concentrated invacuo. The mixture is redissolved in dry acetonitrile and heated toreflux. After 48 h, methanol (5 mL) is added and after 2 h and themixture is evaporated to dryness in vacuo and taken up in 1 M aqueousHCl and ethyl acetate. The aqueous phase is washed with ether. The pH isadjusted to ca. 10 with 2M aqueous sodium hydroxide and it is extractedwith dichloromethane. The combined dichloromethane fractions are driedover MgSO₄, filtered and concentrated in vacuo. The residue is purifiedby silica gel flash chromatography (elution withdichloromethane-methanol, 19:1 to 9:1) to afford the cis diastereomer.MS (ESI) m/z 363 (M+H); ¹H NMR (400 MHz, CDCl₃) (HCl salt) δ ppm1.17-1.27 (m, 1H), 1.84 (dt, J=14.1, 10.9 Hz, 1H), 1.98-2.10 (m, 2H),2.25 (d, J=14.1° Hz, 1H), 2.53-2.65 (m, 3H), 3.01 (ddd, J=15.4, 6.3, 1.8Hz, 1H), 379 (s, 6H), 4.89 (d, J=10.4 Hz, 1H), 6.44-6.52 (m, 3H), 6.76(br s, 2H), 7.11-7.22 (m; 3H), 7.25-730 (m, 2H)

OTHER EMBODIMENTS

Other embodiments will be evident to those of skill in the art. Itshould be understood that the foregoing detailed description is providedfor clarity only and is merely exemplary. The spirit and scope of thepresent invention are not limited to the above examples, but areencompassed by the following claims.

1. A compound of formula (II)

wherein R is hydrogen, (C₁-C₇) alkyl, or (C₂-C₇) alkenyl, said (C₁-C₇)alkyl and (C₂-C₇) alkenyl being optionally substituted by one to fivesubstituents independently selected from the group consisting of —O—R₈and —N(R₈)(R₉), wherein R₅ and R₉ are independently selected from thegroup consisting of hydrogen, (C₁-C₇) alkyl, acyl, aryl and heteroaryl,each of which is further optionally substituted by one to foursubstituents independently selected from the group consisting of halo,(C₁-C₇) alkoxy and (C₁-C₇) alkyl; or R is —C(O)O—R₁₀, or—C(O)N(R₁₁)(R₁₂), wherein R₁₀, R₁₁ and R₁₂ are selected independentlyfrom the group consisting of hydrogen, (C₁-C₇) alkyl, (C₃-C₈)cycloalkyl, aryl, aryl-(C₁-C₇) alkyl, (C₁-C₇) haloalkyl and heteroaryl,each of which is further optionally substituted by one to foursubstituents independently selected from the group consisting of halo,hydroxyl, (C₁-C₇) alkoxy, (C₁-C₇) alkyl, and aryl, wherein R₁₁ and R₁₂taken together with the nitrogen atom to which they are attachedoptionally form a 3-8-membered ring; R₁, R₂, R₃, R₄, and R₅ are selectedindependently from the group consisting of hydrogen, (C₂-C₇) alkenyl,(C₁-C₇) alkyl, (C₃-C₈) cycloalkyl, halo, cyano, nitro, H₂N—, (C₁-C₇)haloalkyl, (C₁-C₇) alkoxy, (C₃-C₈) cycloalkoxy, aryloxy, aryl,heretoaryl, —C(O)OR₁₀, and —N(R₁₃)(R₁₄), said (C₁-C₇) alkyl, (C₂-C₇)alkenyl, (C₁-C₇) alkoxy, aryl and heteroaryl being further optionallysubstituted by one to three substituents selected from (C₁-C₇) alkyl,hydroxyl, halo, (C₁-C₇) alkoxy, nitro, cyano, (C₁-C₇) dialkylamino,(C₁-C₇) alkoxy-(C₁-C₇) alkyl-, and (C₁-C₇) haloalkyl, said R₁₀ havingthe same meanings as defined above, said R₁₃ and R₁₄ are independentlyselected from the group consisting of hydrogen, (C₁-C₇) alkyl, (C₃-C₈)cycloalkyl, (C₁-C₇) haloalkyl, (C₁-C₇) haloalkoxy, aryl and cyano, withthe proviso that no more than three of R₁, R₂, R₃, R₄, and R₅ aresimultaneously hydrogen; R₁₃ and R₁₄ taken together with the nitrogenatom to which they are attached optionally form a 3-8-membered ring; R₆and R₇ are independently hydrogen, hydroxyl, (C₁-C₇) alkyl, (C₁-C₇)alkoxy, phenyl, or benzyl, wherein phenyl and benzyl are optionallysubstituted by one to four substituents independently selected from thegroup consisting of halo, (C₁-C₇) alkoxy and (C₁-C₇) alkyl; when R₆ andR₇ are attached to the same carbon atom, they optionally form a moiety(A) represented by the following structure:

wherein R_(a) and R_(b) are independently hydrogen, (C₁-C₇) alkyl,(C₁-C₇) alkoxy, acyl, —COOR₁₅ or —COR₁₅, said R₁₅ being hydrogen,(C₁-C₇) alkyl, (C₁-C₇) haloalkyl, aryl, or —NH₂; or when R₆ and R₇ areattached to the same carbon atom, they taken together with said carbonatom optionally form a 3-8-membered ring; where acyl where mentionedabove is R—C(O)— of from 1 to 10 carbon atoms of a straight, branched,or cyclic configuration or a combination thereof, attached to the parentstructure through carbonyl functionality, which group may be saturatedor unsaturated, and aliphatic or aromatic, aryl where mentioned aboverefers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-20carbon atoms in the ring portion; heteroaryl where mentioned aboverefers to a 5-14 membered monocyclic- or bicyclic- or fusedpolycyclic-ring system, having 1 to 8 heteroatoms selected from N, O orS; or a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers; or a compound selected fromthe group consisting of:5-(3-fluoro-4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester,5-(3-fluoro-4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole;1-[5-cyano-3-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-yl)phenyl]-3-ethylurea;5-(2-bromo-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid cyclohexylmethylamide; or a pharmaceutically acceptable saltthereof; or an optical isomer thereof; or a mixture of optical isomers.2. The compound of claim 1, wherein R is hydrogen, (C₁-C₄) alkyl,(C₂-C₄) alkenyl, —C(O)O—R₁₀, or —C(O)N(R₁₁)(R₁₂), said (C₁-C₄) alkyl and(C₂-C₄) alkenyl are optionally substituted by one to three substituentsindependently selected from hydroxyl, (C₁-C₄) alkoxy, halo, —NH₂, or(C₁-C₄) dialkylamino; wherein R₁₀, R₁₁ and R₁₂ are independentlyhydrogen, (C₁-C₄) alkyl, (C₆-C₁₀) aryl-(C₁-C₄) alkyl-, (C₃-C₈)cycloalkyl, or (C₂-C₄) alkenyl, each of which is optionally substitutedby one to three substituents independently selected from halo, hydroxyl,or (C₁-C₄) alkoxy; wherein R₁₁ and R₁₂ taken together with the nitrogenatom to which they are attached optionally form a 3-8-membered ring; R₁,R₂, R₃, R₄, and R₅ are independently selected from hydrogen, halo,cyano, —NH₂, (C₁-C₄) dialkylamino, (C₁-C₄) alkoxy, (C₂-C₄) alkenyl,(C₁-C₄) alkyl, (C₁-C₄) haloalkyl, (C₆-C₁₀) aryl, or (5-9)-memberedheteroaryl, said (C₁-C₄) alkoxy, (C₂-C₄) alkenyl, (C₁-C₄) alkyl and(C₆-C₁₀) aryl being optionally substituted by one to three substituentsindependently selected from halo, (C₁-C₄) alkoxy, (C₁-C₄) alkyl, —NH₂,cyano, nitro, (C₁-C₄) alkoxy-(C₁-C₄) alkyl-, or (C₁-C₄) haloalkyl, withthe proviso that no more than three of R₁, R₂, R₃, R₄, and R₅ aresimultaneously hydrogen; R and R₁ taken together optionally form a5-6-membered ring containing 0 or 1 heteroatom selected from O, N, or S;R₆ and R₇ are independently hydrogen, (C₁-C₄) alkyl, (C₃-C₈) cycloalkyl,(C₁-C₄) alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionallysubstituted by one to three substituents independently selected fromhalo, (C₁-C₄) alkyl, or (C₁-C₄) alkoxy; when R₆ and R₇ are attached tothe same carbon atom, they optionally form a moiety (A) described above,wherein R_(a) and R_(b) are independently hydrogen, or (C₁-C₄) alkyl, orR_(a) and R_(b) taken together with said carbon atom optionally form a3-8-membered ring; or a pharmaceutically acceptable salt thereof; or anoptical isomer thereof; or a mixture of optical isomers.
 3. The compoundof claim 1, wherein R is hydrogen, (C₁-C₄) alkyl, (C₂-C₄) alkenyl,—C(O)O—R₁₀, or —C(O)N(R₁₁)(R₁₂), said (C₁-C₄) alkyl and (C₂-C₄) alkenylare optionally substituted by one to three substituents independentlyselected from hydroxyl, (C₁-C₄) alkoxy, halo, —NH₂, or (C₁-C₄)dialkylamino; wherein R₁₀, R₁₁ and R₁₂ are independently hydrogen,(C₁-C₄) alkyl, (C₆-C₁₀) aryl-(C₁-C₄) alkyl-, (C₃-C₈) cycloalkyl, or(C₂-C₄) alkenyl, each of which is optionally substituted by one to threesubstituents independently selected from halo, hydroxyl, or (C₁-C₄)alkoxy; wherein R₁₁ and R₁₂ taken together with the nitrogen atom towhich they are attached optionally form a 3-8-membered ring; R₁, R₂, R₃,R₄, and R₅ are independently selected from hydrogen, halo, cyano, —NH₂,(C₁-C₄) dialkylamino, (C₁-C₄) alkoxy, (C₂-C₄) alkenyl, (C₁-C₄) alkyl,(C₁-C₄) haloalkyl, (C₆-C₁₀) aryl, or (5-9)-membered heteroaryl, said(C₁-C₄) alkoxy, (C₂-C₄) alkenyl, (C₁-C₄) alkyl and (C₆-C₁₀) aryl beingoptionally substituted by one to three substituents independentlyselected from halo, (C₁-C₄) alkoxy, (C₁-C₄) alkyl, —NH₂, cyano, nitro,(C₁-C₄) alkoxy-(C₁-C₄) alkyl-, or (C₁-C₄) haloalkyl, with the provisothat no more than three of R₁, R₂, R₃, R₄, and R₅ are simultaneouslyhydrogen; R and R₁ taken together optionally form a 5-6-membered ringcontaining 0 or 1 heteroatom selected from O, N, or S; R₆ and R₇ areindependently hydrogen, (C₁-C₄) alkyl, (C₃-C₈) cycloalkyl, (C₁-C₄)alkoxy, phenyl, or benzyl, said phenyl and benzyl are optionallysubstituted by one to three substituents independently selected fromhalo, (C₁-C₄) alkyl, or (C₁-C₄) alkoxy; when R₆ and R₇ are attached tothe same carbon atom, they optionally form a moiety (A) described above,wherein R_(a) and R_(b) are independently hydrogen, or (C₁-C₄) alkyl, orR_(a) and R_(b) taken together with said carbon atom optionally form a3-8-membered ring; or a pharmaceutically acceptable salt thereof; or anoptical isomer thereof; or a mixture of optical isomers.
 4. A compoundaccording to claim 1 selected from the group consisting of A compoundaccording to claim 1 selected from the group consisting of:4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-ethyl-benzonitrile;4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-ethyl-benzonitrile;4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-methyl-benzonitrile;4-(R)-6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl-3-fluoro-benzonitrile;4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-methoxy-benzonitrile;4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-methoxy-benzonitrile;3-Bromo-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile;3-Chloro-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile;4-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-2-methyl-benzonitrile;3-Amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile;5-(4-Cyano-2-methoxy-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid butyl ester;5-(4-Cyano-2-methoxy-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (4-methoxy-benzyl)-methyl-amide;5-(4-Cyano-2-trifluoromethoxy-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester;5-(4-Cyano-2-methoxy-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid 2-isopropoxy-ethyl ester;5-(2-Chloro-4-cyano-phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid 4-fluoro-benzyl ester;5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid;5-(2-chloro-4-cyanophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxyliacid methyl ester;5-(4-Cyano-2-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid (4-fluorobenzyl)methylamide;5-(4-Cyano-2,5-dimethoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester;3-Chloro-4-[5-(morpholino-4-carbonyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-yl]benzonitrile;5-(4-Cyano-2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylicacid methyl ester; and5-(3-Fluoro-4-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole, ora pharmaceutically acceptable salt thereof.
 5. A compound according toclaim 1 which is4-(R)-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrilein free form, or a pharmaceutically acceptable salt thereof.
 6. Acompound according to claim 1 which is4-(R)-(6,7-Dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile.7. The R enantiomer of a compound of claim 1 which has the formula

in a pharmaceutically acceptable salt form.
 8. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable carriers for use in a method oftreatment of a disease, that depends on aldosterone synthase activity,selected from hypokalemia, hypertension, congestive heart failure,atrial fibrillation, renal failure, restenosis, atherosclerosis,syndrome X, obesity, nephropathy, post-myocardial infarction, coronaryheart diseases, inflammation, increased formation of collagen, fibrosisand remodeling following hypertension and endothelial dysfunction.
 9. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1, or a pharmaceutically acceptable salt thereof,and one or more pharmaceutically acceptable carriers, for use in amethod of treatment of a disease responsive to inhibition of aromataseactivity, wherein the disorder or disease is a estrogen-dependentdisorder or disease selected from gynecomastia, osteoporosis, prostatecancer, endometriosis, uterine fibroids, dysfunctional uterine bleeding,endometrial hyperplasia, polycystic ovarian disease, infertility,fibrocystic breast disease, breast cancer and fibrocystic mastopathy.10. A pharmaceutical composition according to claim 8, comprising atherapeutically effective amount of said compound or pharmaceuticallyacceptable salt thereof and one or two or more therapeutically activeagents selected from angiotensin II receptor antagonist or apharmaceutically acceptable salt thereof, HMG-Co-A reductase inhibitoror a pharmaceutically acceptable salt thereof; angiotensin convertingenzyme (ACE) Inhibitor or a pharmaceutically acceptable salt thereof;calcium channel blocker (CCB) or a pharmaceutically acceptable saltthereof; dual angiotensin converting enzyme/neutral endopeptidase(ACE/NEP) inhibitor or a pharmaceutically acceptable salt thereof;endothelin antagonist or a pharmaceutically acceptable salt thereof;renin inhibitor or a pharmaceutically acceptable salt thereof; diureticor a pharmaceutically acceptable salt thereof; an ApoA-I mimic; ananti-diabetic agent; an obesity-reducing agent; an aldosterone receptorblocker; an endothelin receptor blocker; a CETP inhibitor; an inhibitorof Na-K-ATPase membrane pump; a beta-adrenergic receptor blocker or analpha-adrenergic receptor blocker; a neutral endopeptidase (NEP)inhibitor; and an inotropic agent.
 11. A pharmaceutical compositionaccording to claim 9, comprising a therapeutically effective amount ofsaid compound or pharmaceutically acceptable salt thereof and one or twoor more therapeutically active agents selected from an antiestrogen; ananti-androgen; a gonadorelin agonist; a topoisomerase I inhibitor; atopoisomerase II inhibitor; a microtubule active agent; an alkylatingagent; an anti-neoplastic anti-metabolite; a platin compound; a compoundtargeting/decreasing a protein or lipid kinase activity or a protein orlipid phosphatase activity, a anti-angiogenic compound; a compound whichinduces cell differentiation processes; monoclonal antibodies; acyclooxygenase inhibitor; a bisphosphonate; a heparanase inhibitor; abiological response modifier; an inhibitor of Ras oncogenic isoforms; atelomerase inhibitor; a protease inhibitor, a matrix metalloproteinaseinhibitor, a methionine aminopeptidase inhibitor; a proteasomeinhibitor; agents which target, decrease or inhibit the activity ofFlt-3; an HSP90 inhibitor; antiproliferative antibodies; an HDACinhibitor; a compound which targets, decreases or inhibits theactivity/function of serine/theronine mTOR kinase; a somatostatinreceptor antagonist; an anti-leukemic compound; tumor cell damagingapproaches; an EDG binder; a ribonucleotide reductase inhibitor; anS-adenosylmethionine decarboxylase inhibitor; a monoclonal antibody ofVEGF or VEGFR; photodynamic therapy; an Angiostatic steroid; an implantcontaining corticosteroids; an AT1 receptor antagonist; and an ACEinhibitor.